Pharmaceutical compositions

ABSTRACT

The invention further provides a method for preparing the (+)-α-dihydrotetrabenazine succinate salt.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.15/939,826 filed Mar. 29, 2018 which claims priority to Great BritainApplication No. 1705303.4, filed on Apr. 1, 2017. The entire contents ofeach of the prior applications are hereby incorporated herein byreference.

This invention relates to a novel dihydrotetrabenazine salt,pharmaceutical compositions containing it, processes for making it andits therapeutic use, for example in the treatment of hyperkineticmovement disorders such as Tourette's syndrome.

BACKGROUND OF THE INVENTION

Movement disorders can generally be classified into two categories:hyperkinetic movement disorders and hypokinetic movement disorders.Hyperkinetic movement disorders are caused by an increase in muscularactivity and can cause abnormal and/or excessive movements, includingtremors, dystonia, chorea, tics, myoclonus and stereotypes.

Hyperkinetic movement disorders often are often psychological in natureand arise through improper regulation of amine neurotransmitters in thebasal ganglia.

Tourette's syndrome is an inherited neurological condition characterisedby multiple physical and vocal tics. The tics are usually repetitive,but random, physical movements or vocal noises. The vocal tics can be ofvarious forms and include repeating one's own words, the words of othersor other sounds. Onset usually occurs in children and continues throughto adolescence and adulthood.

While the tics associated with Tourette's syndrome are temporarilysuppressible, those affected can usually only supress their tics forlimited time periods. There is yet to be an effective treatment to coverall types of tics in all patients, but certain medicaments for ticsuppression have been developed.

It is known that dopamine receptor antagonists display an ability tosupress tics in Tourette's syndrome patients and a number dopaminereceptor antagonists are currently used in the suppression of Tourette'stics, such as fluphenazine, risperidone, haloperidol and pimozide.

Type 2 vesicular monoamine transporter (VMAT2) is a membrane proteinresponsible for the transportation of monoamine neurotransmitters, suchas dopamine, serotonin and histamine, from cellular cytosol intosynaptic vesicles. Inhibition of this protein hinders presynapticneurons from releasing dopamine, resulting in a depletion of dopaminelevels in the brain.

It is therefore to be expected that VMAT2 inhibitors may be effectiveagents against the symptoms of Tourette's syndrome.

Tetrabenazine (Chemical name:1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo(a)quinolizin-2-one)has been in use as a pharmaceutical drug since the late 1950s. Initiallyused as an anti-psychotic, tetrabenazine is currently used for treatinghyperkinetic movement disorders such as Huntington's disease,hemiballismus, senile chorea, tic, tardive dyskinesia and Tourette'ssyndrome, see for example Jankovic et al., Am. J. Psychiatry. (1999)August; 156(8):1279-81 and Jankovic et al., Neurology (1997) February;48(2):358-62.

The primary pharmacological action of tetrabenazine is to reduce thesupply of monoamines (e.g. dopamine, serotonin, and norepinephrine) inthe central nervous system by inhibiting the human vesicular monoaminetransporter isoform 2 (hVMAT2). The drug also blocks postsynapticdopamine receptors.

Tetrabenazine is an effective and safe drug for the treatment of avariety of hyperkinetic movement disorders and, in contrast to typicalneuroleptics, has not been demonstrated to cause tardive dyskinesia.Nevertheless, tetrabenazine does exhibit a number of dose-related sideeffects including causing depression, parkinsonism, drowsiness,nervousness or anxiety, insomnia and, in rare cases, neurolepticmalignant syndrome.

The central effects of tetrabenazine closely resemble those ofreserpine, but it differs from reserpine in that it lacks activity atthe VMAT1 transporter. The lack of activity at the VMAT1 transportermeans that tetrabenazine has less peripheral activity than reserpine andconsequently does not produce VMAT1-related side effects such ashypotension.

The chemical structure of tetrabenazine is as shown below.

Structure of Tetrabenazine

The compound has chiral centres at the 3 and 11b carbon atoms and hencecan, theoretically, exist in a total of four isomeric forms, as shownbelow.

Possible Tetrabenazine Isomers

The stereochemistry of each isomer is defined using the “R and S”nomenclature developed by Cahn, Ingold and Prelog, see Advanced OrganicChemistry by Jerry March, 4^(th) Edition, John Wiley & Sons, New York,1992, pages 109-114. In this patent application, the designations “R” or“S” are given in the order of the position numbers of the carbon atoms.Thus, for example, RS is a shorthand notation for 3R,11bS. Similarly,when three chiral centres are present, as in the dihydrotetrabenazinesdescribed below, the designations “R” or “S” are listed in the order ofthe carbon atoms 2, 3 and 1 lb. Thus, the 2R,3S,11bS isomer is referredto in short hand form as RSS and so on.

Commercially available tetrabenazine is a racemic mixture of the RR andSS isomers and it would appear that the RR and SS isomers are the mostthermodynamically stable isomers.

Tetrabenazine has somewhat poor and variable bioavailability. It isextensively metabolised by first-pass metabolism, and little or nounchanged tetrabenazine is typically detected in the urine. It is knownthat at least some of the metabolites of tetrabenazine aredihydrotetrabenazines formed by reduction of the 2-keto group intetrabenazine.

Dihydrotetrabenazine (Chemical name:2-hydroxy-3-(2-methylpropyl)-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-benzo(a)quinolizine)has three chiral centres and can therefore exist in any of the followingeight optical isomeric forms:

Dihydrotetrabenazine Isomers

The synthesis and characterisation of all eight dihydrotetrabenazineisomers is described by Sun et al. (Eur. J. Med. Chem. (2011),1841-1848).

Of the eight dihydrotetrabenazine isomers, four isomers are derived fromthe more stable RR and SS isomers of the parent tetrabenazine, namelythe RRR, SSS, SRR and RSS isomers.

The RRR and SSS isomers are commonly referred to as “alpha (a)”dihydrotetrabenazines and can be referred to individually as(+)-α-dihydrotetrabenazine and (−)-α-dihydrotetrabenazine respectively.The alpha isomers are characterised by a trans relative orientation ofthe hydroxyl and 2-methylpropyl substituents at the 2- and3-positions—see for example, Kilbourn et al., Chirality, 9:59-62 (1997)and Brossi et al., Helv. Chim. Acta., vol. XLI, No. 193, pp 1793-1806(1958).

The SRR and RSS isomers are commonly referred to as “beta (p)” isomersand can be referred to individually as (+)-β-dihydrotetrabenazine and(−)-β-dihydrotetrabenazine respectively. The beta isomers arecharacterised by a cis relative orientation of the hydroxyl and2-methylpropyl substituents at the 2- and 3-positions.

Although dihydrotetrabenazine is believed to be primarily responsiblefor the activity of the drug, there have been no studies published todate that contain evidence demonstrating which of the variousstereoisomers of dihydrotetrabenazine is responsible for its biologicalactivity. More specifically, there have been no published studiesdemonstrating which of the stereoisomers is responsible for the abilityof tetrabenazine to treat movement disorders such as Tourette'ssyndrome.

Schwartz et al. (Biochem. Pharmacol. (1966), 15: 645-655) describesmetabolic studies of tetrabenazine carried out in rabbits, dogs andhumans. Schwartz et al. identified nine metabolites, five of which wereunconjugated and the other four of which were conjugated with glucuronicacid. The five unconjugated metabolites were the alpha- andbeta-dihydrotetrabenazines, their two oxidised analogues in which ahydroxyl group has been introduced into the 2-methylpropyl side chain,and oxidised tetrabenazine in which a hydroxyl group has been introducedinto the 2-methylpropyl side chain. The four conjugated metabolites wereall compounds in which the 9-methoxy group had been demethylated to givea 9-hydroxy compound. The chirality of the various metabolites was notstudied and, in particular, there was no disclosure of the chirality ofthe individual α- and β-isomers.

Scherman et al., (Mol. Pharmacol. (1987), 33, 72-77 describes thestereospecificity of VMAT2 binding between racemic α- andβ-dihydrotetrabenazine. They reported that α-dihydrotetrabenazine had a3- to 4-fold higher affinity for the Chromaffin Granule MonoamineTransporter than the β-isomer, when studied in vitro. However, Schermanet al. does not disclose the resolution or testing of the individualenantiomers of the α- and β-dihydrotetrabenazines.

Mehvar et al. (J. Pharm. Sci. (1987), 76(6), 461-465) reported a studyof the concentrations of tetrabenazine and dihydrotetrabenazine in thebrains of rats following administration of either tetrabenazine ordihydrotetrabenazine. The study showed that despite its greaterpolarity, dihydrotetrabenazine was able to cross the blood-brainbarrier. However, the stereochemistry of the dihydrotetrabenazine wasnot disclosed.

Mehvar et al. (Drug Metabolism and Disposition (1987), 15:2, 250-255)describes studies of the pharmacokinetics of tetrabenazine anddihydrotetrabenazine following administration of tetrabenazine to fourpatients affected by tardive dyskinesia. Oral administration oftetrabenazine resulted in low plasma concentrations of tetrabenazine butrelatively high concentrations of dihydrotetrabenazine. However, thestereochemistry of the dihydrotetrabenazine formed in vivo was notreported.

Roberts et al. (Eur. J. Clin. Pharmacol. (1986), 29: 703-708) describesthe pharmacokinetics of tetrabenazine and its hydroxy-metabolite inpatients treated for involuntary movement disorders. Roberts et al.reported that tetrabenazine was extensively metabolised after oraladministration resulting in very low plasma concentrations oftetrabenazine but much higher concentrations of a hydroxy-metabolite.Although they did not describe the identity of the hydroxy-metabolites,they suggested that the high plasma concentrations of thehydroxy-metabolites may be therapeutically important (since themetabolites were known to be pharmacologically active) and that, in viewof the disclosure in Schwartz et al. (idem), the combination of cis andtrans isomers (i.e. beta and alpha isomers) could be moretherapeutically important than the parent drug.

Michael Kilbourn and collaborators at the University of Michigan MedicalSchool have published a number of studies relating to the variousisomers of dihydrotetrabenazines. In Med. Chem. Res. (1994), 5:113-126,Kilbourn et al. describe the use (+/−)-α-[11C]-dihydrotetrabenazine asin vivo imaging agents for VMAT2 binding studies.

In Eur. J. Pharmacol (1995) 278, 249-252, Kilbourn et al. reportedcompetition binding studies using [3H]-tetrabenazine to study the invitro binding affinity of (+)-, (−)-, and (+/−)-α-DHTBZ. The bindingassays gave a Ki value of 0.97 nM for (+)-α-dihydrotetrabenazine and 2.2μM for (−)-α-dihydrotetrabenazine, thereby showing that the (+) alphaisomer has much greater binding affinity for the VMAT2 receptor than the(−) alpha isomer. However, no studies were reported, or conclusionsdrawn, as to the usefulness of either isomer in the treatment ofmovement disorders such as Tourette's syndrome.

In Chirality (1997) 9:59-62, Kilbourn et al. described studies aimed atidentifying the absolute configuration of (+)-α-dihydrotetrabenazinefrom which they concluded that it has the 2R, 3R, 11bR configurationshown above. They also referred to the Schwartz et al. and Mehvar et al.articles discussed above as indicating that the α- andβ-dihydrotetrabenazines are likely to be the pharmacologically activeagents in the human brain but they drew no explicit conclusions as tothe precise stereochemical identities of the active metabolites oftetrabenazine.

In Synapse (2002), 43:188-194, Kilbourn et al. described the use of(+)-α-[11C]-dihydrotetrabenazine as an agent used to measure specific invivo binding of the VMAT receptor, in “infusion to equilibrium methods”.They found that (−)-α-[11C]-dihydrotetrabenazine produced a uniformbrain distribution, consistent with the earlier observations that thisenantiomer has a low VMAT affinity.

Sun et al. (idem) investigated the VMAT2 binding affinities of all eightdihydrotetrabenazine isomers. They found that all of the dextrorotatoryenantiomers exhibited dramatically more potent VMAT2 binding activitythan their corresponding laevorotatory enantiomers with the most active(+)-α-isomer being found to be the most active. However, Sun et al. didnot carry out any investigations into the relative efficacies of theindividual isomers in treating movement disorders such as Tourette'ssyndrome.

WO2015/120110 (Auspex) describes extended-release formulations that cancontain any of a wide variety of different pharmacological agents,including tetrabenazine and dihydrotetrabenazine. However, there are noworked examples of any dihydrotetrabenazine formulations; but onlyformulations containing tetrabenazine.

WO 2011/153157 (Auspex Pharmaceutical, Inc.) describes deuterated formsof dihydrotetrabenazine. Many deuterated forms of dihydrotetrabenazineare depicted but the application only provides sufficient information toallow a small number of the depicted compounds to be synthesised.Although racemic mixtures of d₆-α-dihydrotetrabenazine andd₆-α-dihydrotetrabenazine are disclosed, these mixtures were notresolved and the properties of the individual (+) and (−) isomers werenot studied. Similarly, WO 2014/047167 (Auspex Pharmaceutical, Inc.)describes a number of deuterated forms of tetrabenazine and itsderivatives. Again, the individual (+) and (−) isomers of deuteratedforms of α- and β-dihydrotetrabenazine were not separated or studied.

It appears therefore that, up to the present, it remains unclear as toprecisely which dihydrotetrabenazine isomers are responsible for thetherapeutic properties resulting from the administration oftetrabenazine.

It has also remained somewhat unclear up until now whether(+)-α-dihydrotetrabenazine will provide a therapeutically useful effectin the treatment of movement disorders such as Tourette's syndromewithout the accompaniment of unwanted side effects such as thosedescribed above. Thus, for example, whereas WO2016/127133 (NeurocrineBiosciences) refers to the Kilbourn et al. article in Chirality (idem)as indicating that (+)-α-dihydrotetrabenazine is the active metaboliteof tetrabenazine. WO2016/127133, it also refers to the studies reportedin Login et al. (1982), Ann. Neurology 12:257-62 and Reches et al., J.Pharmacol. Exp. Ther. (1983), 225:515-521 which indicate thattetrabenazine inhibits presynaptic and postsynaptic dopamine receptorsin the rat brain. It is suggested in WO2016/127133 that this“off-target” activity of tetrabenazine may be responsible for some ofthe observed side effects of tetrabenazine.

As discussed above, it is known that tetrabenazine exhibits a number ofdose-related side effects including causing depression and parkinsonism(see WO2016/127133). It appears that these side-effects may also becaused by VMAT2 inhibition and that consequently it is difficult toseparate the therapeutic effect of tetrabenazine andtetrabenazine-derived compounds from these side-effects (see Miller,“Valbenazine granted breakthrough drug status for treating tardivedyskinesia”, Expert Opin. Investig. Drugs (2015), 24(6), pp. 737-742).

In an attempt to avoid or reduce the side-effects associated withtetrabenazine, a valine ester prodrug of (+)-α-dihydrotetrabenazine hasbeen developed, known by its INN name, Valbenazine. The structure ofValbenazine is shown below:

As disclosed in U.S. Pat. No. 8,039,627, Valbenazine is prepared byreacting (+)-α-dihydrotetrabenazine with carbobenzyloxy-L-valine indichloromethane and 4-dimethylaminopyridine (DMAP) in the presence ofN,N′-dicyclohexylcarbodiimide (DCC) to give the intermediate2-benzyloxycarbonylamino-3-methyl-butyric acid(2R,3R,1bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1-a]isoquinolin-2-ylester. The intermediate is then hydrogenated over palladium on carbon toremove the benzyloxycarbonyl protecting group to give Valbenazine.

Müller (“Valbenazine granted breakthrough drug status for treatingtardive dyskinesia”, Expert Opin. Investig. Drugs (2015), 24(6), pp.737-742) describes a Phase IIb clinical study of Valbenazine (“KINECT1”) in patients suffering from tardive dyskinesia. Although somereduction of symptoms was observed when doses of Valbenazine at 100mg/day were observed, subjects who received 50 mg/day of Valbenazine didnot show any significant signs of improvement, when scored with theabnormal involuntary movement scale (AIMS). Miller concluded that thisstudy was more or less a failure, probably due to low Valbenazinedosing.

In a further study (“KINECT 2”) described in the same paper, subjectswere initially dosed at 25 mg/day, with the dose range increasing to 75mg/day. By the end of the study, when measurements were taken, 21 out of34 of the subjects treated with Valbenazine were being dosed at 75mg/day (O'Brien et al, “Kinect 2: NBI-98854 treatment of moderate tosevere tardive dyskinesia” Mov. Disord. 2014; 29 (Suppl 1):829). Theanalysis does not provide a breakdown of the reduction in abnormalinvoluntary movements in patients who were being treated with 75 mg/dayby the end of the trial and those who were being treated with 25 mg/dayor 50 mg/day by the end of the trial.

A further Phase III trial of Valbenazine, reported by O'Brien et al(“KINECT 3 A randomised, Double-Blind Placebo-Controlled Phase 3 Trialof Valbenazine (NBI-98854) for Tardive Dyskinesia (PL02.003)”, Neurology(2016), 86(16), Supplement PL02.003) investigated the change in abnormalinvoluntary movements in Tardive Dyskinesia sufferers when administeredwith 40 mg or 80 mg of Valbenazine per day. It was found that 80 mg/dayof Valbenazine resulted in a significant improvement in the AbnormalInvoluntary Movement Score and it was concluded that 80 mg/dayValbenazine was associated with a significant improvement in TardiveDyskinesia.

WO 2015/171802 (Neurocrine Biosciences, Inc.) describes methods fortreating hyperkinetic diseases by administering therapeutic agents thatproduce plasma concentrations of (+)-α-dihydrotetrabenazine such thatthere is a C_(max) of between about 15 ng/ml and 60 ng/ml and a C_(min)of at least 15 ng/ml over an eight hour period. Although it is suggestedin WO 2015/171802 that this can be accomplished by administering(+)-α-dihydrotetrabenazine per se, the experiments described in WO2015/171802 only provide data for (+)-α-dihydrotetrabenazine levelsachieved after the administration of Valbenazine. In Example 1 of WO2015/171802, it is concluded that a concentration of 30 ng/ml of(+)-α-dihydrotetrabenazine in plasma is an appropriate target and thatexposures below 15 ng/ml are suboptimal across the general tardivedyskinesia (TD) population. In Example 2 of WO 2015/171802, it isdisclosed that a 50 mg dose of Valbenazine appeared to maintain therequired plasma levels of (+)-α-dihydrotetrabenazine.

WO2016/210180 (Neurocrine Biosciences) discloses the use of VMAT2inhibitors for treating various neurological disorders.(+)-α-dihydrotetrabenazine is mentioned as an example of a VMAT2inhibitor but the VMAT2 inhibitory compounds specifically exemplified inWO2016/210180 are Valbenazine and [(2R, 3S,11bR)-9,10-dimethoxy-3-(2-methylpropyl)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinolin-2-yl]methanol.

Although having a greater solubility than tetrabenazine,(+)-α-dihydrotetrabenazine still possess a relatively low solubility andalso demonstrates a tendency to form polymorphs. Therefore, there existsthe need for pharmaceutical compositions of (+)-α-dihydrotetrabenazinewith improved physical properties.

THE INVENTION

(+)-α-Dihydrotetrabenazine salts are antagonists of VMAT2. Tetrabenazineexerts its therapeutic effects by inhibiting VMAT2 in the brain and byinhibiting both pre-synaptic and post-synaptic dopamine receptors.

The inventors of the present application have found that the(+)-α-dihydrotetrabenazine succinate salt possesses unexpectedly goodphysical properties in comparison with the free base and other commonacid addition salts. In particular, the succinate salt has a highersolubility and a greater thermal stability, with a reduced tendency toform polymorphs, than the free base and other common salts.

On the basis of the studies carried out to date, it is envisaged thatthe succinate salt of (+)-α-dihydrotetrabenazine will be useful in theprophylaxis or treatment of the disease states and conditions for whichtetrabenazine is currently used or proposed. Thus, by way of example,and without limitation, the (+)-α-dihydrotetrabenazine succinate salt ofthe invention may be used for the treatment of hyperkinetic movementdisorders such as Huntington's disease, hemiballismus, senile chorea,tic disorders, tardive dyskinesia, dystonia and Tourette's syndrome. Itis also envisaged that the dihydrotetrabenazine succinate salt of theinvention may be useful in the treatment of depression.

(+)-α-Dihydrotetrabenazine is believed to have the chemical structure(I) shown in formula (I) below:

Accordingly, the invention provides (+)-α-dihydrotetrabenazinesuccinate, which has a chemical formula as shown in Formula (II).

In this application, (+)-α-dihydrotetrabenazine succinate may bereferred to for convenience and brevity as (+)-α-DHTBZ succinate or(+)-α-DHTBZ succinate salt, or the succinate salt of the invention.

The succinate salt of the invention typically has a salt ratio (molarratio of (+)-α-dihydrotetrabenazine free base to the acid) ofapproximately 1:1.

In another aspect, the invention provides a pharmaceutical compositioncomprising (+)-α-dihydrotetrabenazine succinate and a pharmaceuticallyacceptable excipient.

The invention also provides:

-   -   (+)-α-dihydrotetrabenazine succinate for use in medicine.    -   (+)-α-dihydrotetrabenazine succinate for use as a VMAT2 receptor        antagonist.    -   (+)-α-Dihydrotetrabenazine succinate for use in the treatment of        a movement disorder (e.g. a hyperkinetic movement disorder).    -   A method of treatment of a movement disorder (e.g. a        hyperkinetic movement disorder) in a subject in need thereof        (e.g. a mammalian subject such as a human), which method        comprises administering to the subject a therapeutically        effective amount of (+)-α-dihydrotetrabenazine succinate.    -   The use of (+)-α-dihydrotetrabenazine succinate for the        manufacture of a medicament for the treatment of a movement        disorder (e.g. a hyperkinetic movement disorder).    -   A unit dosage form (for example a capsule or a tablet)        comprising (+)-α-dihydrotetrabenazine succinate and a        pharmaceutically acceptable excipient.

The (+)-α-dihydrotetrabenazine succinate may be used in the treatment ofa hyperkinetic movement disorder such as Huntington's disease,hemiballismus, senile chorea, tic disorders, tardive dyskinesia,dystonia and Tourette's syndrome. In one embodiment, the hyperkineticmovement order is Tourette's syndrome.

The (+)-α-dihydrotetrabenazine succinate described herein typically hasan isomeric purity of greater than 60%.

The term “isomeric purity” in the present context refers to the amountof (+)-α-dihydrotetrabenazine free base present in the succinate saltrelative to the total amount or concentration of dihydrotetrabenazine ofall isomeric forms. For example, if 90% of the totaldihydrotetrabenazine present in the composition is(+)-α-dihydrotetrabenazine, then the isomeric purity is 90%.

The (+)-α-dihydrotetrabenazine salt of the invention may have anisomeric purity of greater than 82%, greater than 85%, greater than 87%,greater than 90%, greater than 91%, greater than 92%, greater than 93%,greater than 94%, greater than 95%, greater than 96%, greater than 97%,greater than 98%, greater than 99%, greater than 99.5%, or greater than99.9%.

The (+)-α-dihydrotetrabenazine succinate will generally be administeredto a subject in need of such administration, for example a human oranimal patient, preferably a human.

The (+)-α-dihydrotetrabenazine succinate will typically be administeredin amounts that are therapeutically or prophylactically useful and whichgenerally are non-toxic. However, in certain situations, the benefits ofadministering a dihydrotetrabenazine compound of the invention mayoutweigh the disadvantages of any toxic effects or side effects, inwhich case it may be considered desirable to administer compounds inamounts that are associated with a degree of toxicity.

The inventors of the present application have also found that that(+)-α-dihydrotetrabenazine is effective in the treatment of movementdisorders (e.g. a hyperkinetic movement disorder) at much lower dosesthan could have been predicted from the literature (for example from WO2015/171802) and that its use at such lower doses can avoid or minimizethe unwanted side effects associated with tetrabenazine.

More particularly, experiments carried out by the present inventorsindicate that movement disorders such as Tourette's syndrome can betreated effectively by administering much lower doses of(+)-α-dihydrotetrabenazine per se than the doses of Valbenazine requiredin WO 2015/171802.

Accordingly, in another aspect, the invention provides a pharmaceuticalcomposition comprising (+)-α-dihydrotetrabenazine succinate and apharmaceutically acceptable excipient.

The pharmaceutical composition can be, for example, a unit dosage formcomprising from 0.5 mg to 30 mg (e.g. between 0.5 mg and 20 mg) of(+)-α-dihydrotetrabenazine succinate and a pharmaceutically acceptableexcipient.

The unit dosage form can be one which is administered orally, forexample a capsule or tablet.

In particular embodiments of the invention, there is provided:

-   -   A unit dosage form comprising from 0.5 mg to 30 mg (e.g. between        0.5 mg and 30 mg) of (+)-α-dihydrotetrabenazine succinate and a        pharmaceutically acceptable excipient.    -   A unit dosage form comprising from 0.5 mg to 25 mg (e.g. between        0.5 mg and 25 mg) of (+)-α-dihydrotetrabenazine succinate and a        pharmaceutically acceptable excipient.    -   A unit dosage form comprising from 0.5 mg to 20 mg (e.g. between        0.5 mg and 20 mg) of (+)-α-dihydrotetrabenazine succinate and a        pharmaceutically acceptable excipient.    -   A unit dosage form comprising from 1 mg to 30 mg (e.g. between 1        mg and 30 mg) of (+)-α-dihydrotetrabenazine succinate and a        pharmaceutically acceptable excipient.    -   A unit dosage form comprising from 1 mg to 25 mg (e.g. between 1        mg and 25 mg) of (+)-α-dihydrotetrabenazine succinate and a        pharmaceutically acceptable excipient.    -   A unit dosage form comprising from 1 mg to 20 mg (e.g. between 1        mg and 20 mg) of (+)-α-dihydrotetrabenazine succinate and a        pharmaceutically acceptable excipient.    -   A unit dosage form comprising from 2 mg to 20 mg (e.g. between 2        mg and 20 mg) of (+)-α-dihydrotetrabenazine succinate and a        pharmaceutically acceptable excipient.    -   A unit dosage form comprising from 0.5 mg to 10 mg (e.g. between        0.5 mg and 10 mg) of (+)-α-dihydrotetrabenazine succinate and a        pharmaceutically acceptable excipient.    -   A unit dosage form comprising from 0.5 mg to 7.5 mg (e.g.        between 0.5 mg and 7.5 mg) of (+)-α-dihydrotetrabenazine        succinate and a pharmaceutically acceptable excipient.    -   A unit dosage form comprising from 1 mg to 10 mg (e.g. between 1        mg and 10 mg) of (+)-α-dihydrotetrabenazine succinate and a        pharmaceutically acceptable excipient.    -   A unit dosage form comprising from 1 mg to 7.5 mg (e.g. between        1 mg and 7.5 mg) of (+)-α-dihydrotetrabenazine succinate and a        pharmaceutically acceptable excipient.    -   A unit dosage form comprising from 3 mg to 20 mg (e.g. between 3        mg and 20 mg) of (+)-α-dihydrotetrabenazine succinate and a        pharmaceutically acceptable excipient.    -   A unit dosage form comprising from 2 mg to 15 mg (e.g. between 2        mg and 15 mg) of (+)-α-dihydrotetrabenazine succinate and a        pharmaceutically acceptable excipient.    -   A unit dosage form comprising from 3 mg to 15 mg (e.g. between 3        mg and 15 mg) of (+)-α-dihydrotetrabenazine succinate and a        pharmaceutically acceptable excipient.    -   A unit dosage form comprising from 4 mg to 15 mg (e.g. between 4        mg and 15 mg) of (+)-α-dihydrotetrabenazine succinate and a        pharmaceutically acceptable excipient.    -   A unit dosage form comprising from 5 mg to 15 mg (e.g. between 5        mg and 15 mg) of (+)-α-dihydrotetrabenazine succinate and a        pharmaceutically acceptable excipient.    -   A unit dosage form comprising approximately 0.5 mg of        (+)-α-dihydrotetrabenazine succinate and a pharmaceutically        acceptable excipient.    -   A unit dosage form comprising approximately 1 mg of        (+)-α-dihydrotetrabenazine succinate and a pharmaceutically        acceptable excipient.    -   A unit dosage form comprising approximately 2 mg of        (+)-α-dihydrotetrabenazine succinate and a pharmaceutically        acceptable excipient.    -   A unit dosage form comprising approximately 3 mg of        (+)-α-dihydrotetrabenazine succinate and a pharmaceutically        acceptable excipient.    -   A unit dosage form comprising approximately 4 mg of        (+)-α-dihydrotetrabenazine succinate and a pharmaceutically        acceptable excipient.    -   A unit dosage form comprising approximately 5 mg of        (+)-α-dihydrotetrabenazine succinate and a pharmaceutically        acceptable excipient.    -   A unit dosage form comprising approximately 7.5 mg of        (+)-α-dihydrotetrabenazine succinate and a pharmaceutically        acceptable excipient.    -   A unit dosage form comprising approximately 10 mg of        (+)-α-dihydrotetrabenazine succinate and a pharmaceutically        acceptable excipient.    -   A unit dosage form comprising approximately 12.5 mg of        (+)-α-dihydrotetrabenazine succinate and a pharmaceutically        acceptable excipient.    -   A unit dosage form comprising approximately 15 mg of        (+)-α-dihydrotetrabenazine succinate and a pharmaceutically        acceptable excipient.

The unit dosage forms may be administered orally and may be capsules ortablets.

The unit dosage forms defined and described above are typically for usein the treatment of a hyperkinetic movement disorder such asHuntington's disease, hemiballismus, senile chorea, tic disorders,tardive dyskinesia, dystonia and Tourette's syndrome.

The invention also provides:

-   -   (+)-α-dihydrotetrabenazine succinate for use in a method for the        treatment of a movement disorder (e.g. a hyperkinetic movement        disorder), wherein the treatment comprises administering to a        subject an amount of (+)-α-dihydrotetrabenzine succinate between        1 mg and 30 mg per day.    -   A method of treatment of a movement disorder (e.g. a        hyperkinetic movement disorder) in a subject in need thereof        (e.g. a mammalian subject such as a human), which treatment        comprises administering to the subject an amount of        (+)-α-dihydrotetrabenazine succinate between 1 mg and 30 mg per        day.    -   The use of (+)-α-dihydrotetrabenazine succinate for the        manufacture of a medicament for the treatment of a movement        disorder (e.g. a hyperkinetic movement disorder), which        treatment comprises administering to the subject an amount of        (+)-α-dihydrotetrabenazine succinate between 1 mg and 30 mg per        day.    -   (+)-α-dihydrotetrabenazine succinate for use, a method or a use        as described herein, wherein the treatment comprises        administering to the subject an amount of        (+)-α-dihydrotetrabenazine succinate between 2 mg and 30 mg per        day.    -   (+)-α-dihydrotetrabenazine succinate for use, a method or a use        as described herein, wherein the treatment comprises        administering to the subject an amount of        (+)-α-dihydrotetrabenazine succinate between 3 mg and 30 mg per        day.    -   (+)-α-dihydrotetrabenazine succinate for use, a method or a use        as described herein, wherein the treatment comprises        administering to the subject an amount of        (+)-α-dihydrotetrabenazine succinate between 2 mg and 20 mg per        day.    -   (+)-α-dihydrotetrabenazine succinate for use, a method or a use        as described herein, wherein the treatment comprises        administering to the subject an amount of        (+)-α-dihydrotetrabenazine succinate between 3 mg and 20 mg per        day.    -   (+)-α-dihydrotetrabenazine succinate for use, a method or a use        as described herein, wherein the treatment comprises        administering to the subject an amount of        (+)-α-dihydrotetrabenazine succinate between 5 mg and 20 mg per        day.    -   (+)-α-dihydrotetrabenazine succinate for use, a method or a use        as described herein, wherein the treatment comprises        administering to the subject an amount of        (+)-α-dihydrotetrabenazine of approximately 7.5 mg per day.    -   (+)-α-dihydrotetrabenazine succinate for use, a method or a use        as described herein, wherein the treatment comprises        administering to the subject an amount of        (+)-α-dihydrotetrabenazine succinate of approximately 10 mg per        day.    -   (+)-α-dihydrotetrabenazine succinate for use, a method or a use        as described herein, wherein the treatment comprises        administering to the subject an amount of        (+)-α-dihydrotetrabenazine succinate of approximately 12.5 mg        per day.    -   (+)-α-dihydrotetrabenazine succinate for use, a method or a use        as described herein, wherein the treatment comprises        administering to the subject an amount of        (+)-α-dihydrotetrabenazine succinate of approximately 15 mg per        day.    -   (+)-α-dihydrotetrabenazine succinate for use, a method or a use        as described herein, wherein the treatment comprises        administering to the subject an amount of        (+)-α-dihydrotetrabenazine succinate of approximately 20 mg per        day.    -   In each case, the quantity of (+)-α-dihydrotetrabenazine        succinate specified may be administered once per day or in        several (e.g. two) doses per day.    -   In some embodiments, the quantity of (+)-α-dihydrotetrabenazine        succinate specified is administered once daily.    -   The administration of (+)-α-dihydrotetrabenazine succinate        typically forms part of a chronic treatment regime. The        (+)-α-dihydrotetrabenazine succinate may therefore be        administered to a patient for a treatment period of at least a        week, more usually at least two weeks, or at least a month, and        typically longer than a month. Where a patient is shown to        respond well to treatment, the period of treatment can be longer        than six months and may extend over a period of years.    -   The chronic treatment regime may involve the administration of        the (+)-α-dihydrotetrabenazine succinate every day, or the        treatment regime may include days when no        (+)-α-dihydrotetrabenazine succinate is administered.    -   The dosage administered to the subject may vary during the        treatment period. For example, the initial dosage may be        increased or decreased depending on the subject's response to        the treatment. A subject may, for example, be given an initial        low dose to test the subject's tolerance towards the        (+)-α-dihydrotetrabenazine succinate, and the dosage thereafter        increased as necessary up to a maximum daily intake of 30 mg.        Alternatively, an initial daily dosage administered to the        patient may be selected so as to give an estimated desired        degree of VMAT2 blockage, following which a lower maintenance        dose may be given for the remainder of the treatment period,        with the option of increasing the dosage should the subject's        response to the treatment indicate that an increase is        necessary.

Thus, the invention also provides a method of treating a movementdisorder in a subject in need thereof, and (+)-α-dihydrotetrabenazinesuccinate for use in the method;

which method comprises the steps of:

(a) administering to the subject an initial daily dosage of(+)-α-dihydrotetrabenazine succinate, wherein the initial daily dosageis an amount of (+)-α-dihydrotetrabenazine succinate corresponding tofrom 0.5 mg to 5 mg of (+)-α-dihydrotetrabenazine free base;

(b) carrying out a clinical evaluation of the subject for efficacy andside effects arising from the treatment;

(c) where the clinical evaluation (b) has established that an increaseddaily dosage of (+)-α-dihydrotetrabenazine succinate is desirable,administering an increased daily dosage which is greater than theinitial daily dosage by an incremental amount of(+)-α-dihydrotetrabenazine succinate thereof corresponding to from 0.5mg to 5 mg of (+)-α-dihydrotetrabenazine free base; or, where theclinical evaluation has established that an increased daily dosage isnot desirable, either maintaining the initial daily dosage, reducing thedosage, or discontinuing the treatment;

(d) where an increased daily dosage has been administered, carrying outa further clinical evaluation of the subject for efficacy and sideeffects arising from the treatment with the increased daily dosage;

(e) where the further clinical evaluation (d) has established that afurther increased daily dosage of (+)-α-dihydrotetrabenazine succinateis desirable, administering a further increased daily dosage which isgreater than an immediately preceding daily dosage by an incrementalamount of (+)-α-dihydrotetrabenazine succinate corresponding to from 0.5mg to 5 mg of (+)-α-dihydrotetrabenazine free base; or, where theclinical evaluation has established that a further increased dailydosage is not desirable, maintaining the immediately preceding dailydosage, reducing the immediately preceding dosage or discontinuing thetreatment; and

(f) optionally repeating steps (d) and (e) as often as desired until anoptimum daily dosage is reached.

In particular embodiments of the foregoing method, there are provided:

A method (or (+)-α-dihydrotetrabenazine succinate for use in the method)wherein the initial daily dosage of (+)-α-dihydrotetrabenazinesuccinate, is an amount corresponding to from 0.5 mg to 3 mg of(+)-α-dihydrotetrabenazine free base.

A method (or (+)-α-dihydrotetrabenazine succinate for use in the method)wherein the initial daily dosage of (+)-α-dihydrotetrabenazinesuccinate, is an amount corresponding to from 0.5 mg to 2 mg of(+)-α-dihydrotetrabenazine free base.

A method (or (+)-α-dihydrotetrabenazine succinate for use in the method)wherein the initial daily dosage of (+)-α-dihydrotetrabenazinesuccinate, is an amount corresponding to 0.5 mg, 1 mg, 1.5 mg, or 2 mgof (+)-α-dihydrotetrabenazine free base.

A method (or (+)-α-dihydrotetrabenazine succinate for use in the method)wherein the initial daily dosage of (+)-α-dihydrotetrabenazinesuccinate, is an amount corresponding to 0.5 mg of(+)-α-dihydrotetrabenazine free base.

A method (or (+)-α-dihydrotetrabenazine succinate for use in the method)wherein the initial daily dosage of (+)-α-dihydrotetrabenazinesuccinate, is an amount corresponding to 1 mg of(+)-α-dihydrotetrabenazine free base.

A method (or (+)-α-dihydrotetrabenazine succinate for use in the method)wherein the initial daily dosage of (+)-α-dihydrotetrabenazinesuccinate, is an amount corresponding to 1.5 mg of(+)-α-dihydrotetrabenazine free base.

A method (or (+)-α-dihydrotetrabenazine succinate for use in the method)wherein the initial daily dosage of (+)-α-dihydrotetrabenazinesuccinate, is an amount corresponding to 2 mg of(+)-α-dihydrotetrabenazine free base.

A method (or (+)-α-dihydrotetrabenazine succinate for use in the method)wherein the increased daily dosage in step (c) is an amount which isgreater than the initial daily dosage by an incremental amount of(+)-α-dihydrotetrabenazine succinate corresponding to from 0.5 mg to 3mg of (+)-α-dihydrotetrabenazine free base.

A method (or (+)-α-dihydrotetrabenazine succinate for use in the method)wherein the increased daily dosage in step (c) is an amount which isgreater than the initial daily dosage by an incremental amount of(+)-α-dihydrotetrabenazine succinate corresponding to from 0.5 mg to 2mg of (+)-α-dihydrotetrabenazine free base.

A method (or (+)-α-dihydrotetrabenazine succinate for use in the method)wherein the increased daily dosage in step (c) is an amount which isgreater than the initial daily dosage by an incremental amount of(+)-α-dihydrotetrabenazine succinate corresponding to 0.5 mg, 1 mg, 1.5mg, or 2 mg of (+)-α-dihydrotetrabenazine free base.

A method (or (+)-α-dihydrotetrabenazine succinate for use in the method)wherein the increased daily dosage in step (c) is an amount which isgreater than the initial daily dosage by an incremental amount of(+)-α-dihydrotetrabenazine succinate corresponding to 0.5 mg of(+)-α-dihydrotetrabenazine free base.

A method (or (+)-α-dihydrotetrabenazine succinate for use in the method)wherein the increased daily dosage in step (c) is an amount which isgreater than the initial daily dosage by an incremental amount of(+)-α-dihydrotetrabenazine succinate corresponding to 1 mg of(+)-α-dihydrotetrabenazine free base.

A method (or (+)-α-dihydrotetrabenazine succinate for use in the method)wherein the increased daily dosage in step (c) is an amount which isgreater than the initial daily dosage by an incremental amount of(+)-α-dihydrotetrabenazine succinate corresponding to 1.5 mg of(+)-α-dihydrotetrabenazine free base.

A method (or (+)-α-dihydrotetrabenazine succinate for use in the method)wherein the increased daily dosage in step (c) is an amount which isgreater than the initial daily dosage by an incremental amount of(+)-α-dihydrotetrabenazine succinate corresponding to 2 mg of(+)-α-dihydrotetrabenazine free base.

A method (or (+)-α-dihydrotetrabenazine succinate for use in the method)wherein the further increased daily dosage in step (e) is greater thanan immediately preceding daily dosage by an incremental amount of(+)-α-dihydrotetrabenazine succinate corresponding to from 0.5 mg to 3mg of (+)-α-dihydrotetrabenazine free base.

A method (or (+)-α-dihydrotetrabenazine succinate for use in the method)wherein the further increased daily dosage in step (e) is greater thanan immediately preceding daily dosage by an incremental amount of(+)-α-dihydrotetrabenazine succinate corresponding to from 0.5 mg to 2mg of (+)-α-dihydrotetrabenazine free base.

A method (or (+)-α-dihydrotetrabenazine succinate for use in the method)wherein the further increased daily dosage in step (e) is greater thanan immediately preceding daily dosage by an incremental amount of(+)-α-dihydrotetrabenazine succinate corresponding to 0.5 mg, 1 mg, 1.5mg, or 2 mg of (+)-α-dihydrotetrabenazine free base.

A method (or (+)-α-dihydrotetrabenazine succinate for use in the method)wherein the further increased daily dosage in step (e) is greater thanan immediately preceding daily dosage by an incremental amount of(+)-α-dihydrotetrabenazine succinate corresponding to 0.5 mg of(+)-α-dihydrotetrabenazine free base.

A method (or (+)-α-dihydrotetrabenazine succinate for use in the method)wherein the further increased daily dosage in step (e) is greater thanan immediately preceding daily dosage by an incremental amount of(+)-α-dihydrotetrabenazine succinate corresponding to 1 mg of(+)-α-dihydrotetrabenazine free base.

A method (or (+)-α-dihydrotetrabenazine succinate for use in the method)wherein the further increased daily dosage in step (e) is greater thanan immediately preceding daily dosage by an incremental amount of(+)-α-dihydrotetrabenazine succinate corresponding to 1.5 mg of(+)-α-dihydrotetrabenazine free base.

A method (or (+)-α-dihydrotetrabenazine succinate for use in the method)wherein the further increased daily dosage in step (e) is greater thanan immediately preceding daily dosage by an incremental amount of(+)-α-dihydrotetrabenazine succinate corresponding to 2 mg of(+)-α-dihydrotetrabenazine free base.

A method (or (+)-α-dihydrotetrabenazine succinate for use in the method)wherein the treatment comprises the administration of a maximum (e.g.optimized) daily dosage of (+)-α-dihydrotetrabenazine succinate, whichis an amount corresponding to no greater than 20 mg of(+)-α-dihydrotetrabenazine free base.

A method (or (+)-α-dihydrotetrabenazine succinate for use in the method)wherein the treatment comprises the administration of a maximum (e.g.optimized) daily dosage of (+)-α-dihydrotetrabenazine succinate, whichis an amount corresponding to no greater than 17.5 mg of(+)-α-dihydrotetrabenazine free base.

A method (or (+)-α-dihydrotetrabenazine succinate for use in the method)wherein the treatment comprises the administration of a maximum (e.g.optimized) daily dosage of (+)-α-dihydrotetrabenazine succinate, whichis an amount corresponding to no greater than 15 mg of(+)-α-dihydrotetrabenazine free base.

A method (or (+)-α-dihydrotetrabenazine succinate for use in the method)wherein the treatment comprises the administration of a maximum (e.g.optimized) daily dosage of (+)-α-dihydrotetrabenazine succinate, whichis an amount corresponding to no greater than 12.5 mg of(+)-α-dihydrotetrabenazine free base.

A method (or (+)-α-dihydrotetrabenazine succinate for use in the method)wherein the treatment comprises the administration of a maximum (e.g.optimized) daily dosage of (+)-α-dihydrotetrabenazine succinate, whichis an amount corresponding to no greater than 10 mg of(+)-α-dihydrotetrabenazine free base.

A method (or (+)-α-dihydrotetrabenazine succinate for use in the method)wherein the treatment comprises the administration of a maximum (e.g.optimized) daily dosage of (+)-α-dihydrotetrabenazine succinate, whichis an amount corresponding to no greater than 9 mg of(+)-α-dihydrotetrabenazine free base.

A method (or (+)-α-dihydrotetrabenazine succinate for use in the method)wherein the treatment comprises the administration of a maximum (e.g.optimized) daily dosage of (+)-α-dihydrotetrabenazine succinate, whichis an amount corresponding to no greater than 8 mg of(+)-α-dihydrotetrabenazine free base.

A method (or (+)-α-dihydrotetrabenazine succinate for use in the method)wherein the treatment comprises the administration of a maximum (e.g.optimized) daily dosage of (+)-α-dihydrotetrabenazine succinate, whichis an amount corresponding to no greater than 7.5 mg of(+)-α-dihydrotetrabenazine free base.

A method (or (+)-α-dihydrotetrabenazine succinate for use in the method)wherein the treatment comprises the administration of a maximum (e.g.optimized) daily dosage of (+)-α-dihydrotetrabenazine succinate, whichis an amount corresponding to no greater than 7 mg of(+)-α-dihydrotetrabenazine free base.

A method (or (+)-α-dihydrotetrabenazine succinate for use in the method)wherein the treatment comprises the administration of a maximum (e.g.optimized) daily dosage of (+)-α-dihydrotetrabenazine succinate, whichis an amount corresponding to no greater than 6 mg of(+)-α-dihydrotetrabenazine free base.

A method (or (+)-α-dihydrotetrabenazine succinate for use in the method)wherein the treatment comprises the administration of a maximum (e.g.optimized) daily dosage of (+)-α-dihydrotetrabenazine succinate, whichis an amount corresponding to no greater than 5 mg of(+)-α-dihydrotetrabenazine free base.

A method (or (+)-α-dihydrotetrabenazine succinate for use in the method)wherein the treatment comprises the administration of a maximum (e.g.optimized) daily dosage of (+)-α-dihydrotetrabenazine succinate, whichis an amount corresponding to no greater than 4 mg of(+)-α-dihydrotetrabenazine free base.

A method (or (+)-α-dihydrotetrabenazine succinate for use in the method)wherein the treatment comprises the administration of a maximum (e.g.optimized) daily dosage of (+)-α-dihydrotetrabenazine succinate, whichis an amount corresponding to no greater than 3 mg of(+)-α-dihydrotetrabenazine free base.

A method (or (+)-α-dihydrotetrabenazine succinate for use in the method)wherein the treatment comprises the administration of a maximum (e.g.optimized) daily dosage of (+)-α-dihydrotetrabenazine succinate, whichis an amount corresponding to no greater than 2.5 mg of(+)-α-dihydrotetrabenazine free base.

The quantity of (+)-α-dihydrotetrabenazine succinate required to achievethe desired therapeutic effect may be dependent on the weight of thesubject to be treated. The quantities of (+)-α-dihydrotetrabenazinesuccinate administered to the subject can be expressed as the number ofmg/kg, where “mg” refers to the weight of active compound (i.e. the(+)-α-dihydrotetrabenazine free base component of the salt) and “kg”refers to the weight of the subject to be treated. The appropriatedosage amount can therefore be calculated by multiplying the mg/kgamount by the weight of the subject to be treated. Accordingly, theinvention also provides:

-   -   (+)-α-dihydrotetrabenazine succinate for use in a method for the        treatment of a movement disorder, wherein the treatment        comprises administering to a subject an amount of        (+)-α-dihydrotetrabenazine succinate salt corresponding to        between 0.01 mg/kg and 0.5 mg/kg per day of        (+)-α-dihydrotetrabenazine free base provided that the total        amount of (+)-α-dihydrotetrabenazine succinate administered per        day is in the range from 1 mg to 30 mg (e.g. from 1 mg to 20        mg).    -   A method of treatment of a movement disorder in a subject in        need thereof (e.g. a mammalian subject such as a human), which        treatment comprises administering to the subject an amount of        (+)-α-dihydrotetrabenazine succinate corresponding to between        0.01 mg/kg and 0.5 mg/kg per day of (+)-α-dihydrotetrabenazine        free base, provided that the total amount of        (+)-α-dihydrotetrabenazine succinate administered per day is in        the range from 1 mg to 30 mg (e.g. from 1 mg to 20 mg).    -   The use of (+)-α-dihydrotetrabenazine succinate for the        manufacture of a medicament for the treatment of a movement        disorder, which treatment comprises administering to the subject        an amount of (+)-α-dihydrotetrabenazine succinate corresponding        to between 0.01 mg/kg and 0.5 mg/kg (+)-α-dihydrotetrabenazine        free base, provided that the total amount of        (+)-α-dihydrotetrabenazine succinate administered per day is in        the range from 1 mg to 30 mg (e.g. from 1 mg to 20 mg).

In further embodiments, there is provided:

-   -   (+)-α-dihydrotetrabenazine succinate for use, a method or a use        as described herein, wherein the treatment comprises        administering to the subject an amount of        (+)-α-dihydrotetrabenazine succinate corresponding to between        0.01 mg/kg and 0.3 mg/kg of (+)-α-dihydrotetrabenazine free base        per day, provided that the total amount of        (+)-α-dihydrotetrabenazine succinate administered per day is in        the range from 0.5 mg to 20 mg (e.g. 1 mg to 20 mg).    -   (+)-α-dihydrotetrabenazine succinate for use, a method or a use        as described herein, wherein the treatment comprises        administering to the subject an amount of        (+)-α-dihydrotetrabenazine succinate corresponding to between        0.02 mg/kg and 0.3 mg/kg of (+)-α-dihydrotetrabenazine free base        per day, provided that the total amount of        (+)-α-dihydrotetrabenazine succinate administered per day is in        the range from 0.5 mg to 20 mg (e.g. 1 mg to 20 mg).    -   (+)-α-dihydrotetrabenazine succinate for use, a method or a use        as described herein, wherein the treatment comprises        administering to the subject an amount of        (+)-α-dihydrotetrabenazine succinate corresponding to between        0.03 mg/kg and 0.3 mg/kg of (+)-α-dihydrotetrabenazine free        base, provided that the total amount of        (+)-α-dihydrotetrabenazine succinate administered per day is in        the range from 0.5 mg to 20 mg (e.g. 1 mg to 20 mg).    -   (+)-α-dihydrotetrabenazine succinate for use, a method or a use        as described herein, wherein the treatment comprises        administering to the subject an amount of        (+)-α-dihydrotetrabenazine succinate corresponding to between        0.04 mg/kg and 0.3 mg/kg of (+)-α-dihydrotetrabenazine free        base, provided that the total amount of        (+)-α-dihydrotetrabenazine succinate administered per day is in        the range from 0.5 mg to 20 mg (e.g. 1 mg to 20 mg).    -   (+)-α-dihydrotetrabenazine succinate for use, a method or a use        as described herein, wherein the treatment comprises        administering to the subject an amount of        (+)-α-dihydrotetrabenazine succinate corresponding to between        0.05 mg/kg and 0.3 mg/kg of (+)-α-dihydrotetrabenazine free        base, provided that the total amount of        (+)-α-dihydrotetrabenazine succinate administered per day is in        the range from 0.5 mg to 20 mg (e.g. 1 mg to 20 mg).    -   (+)-α-dihydrotetrabenazine succinate for use, a method or a use        as described herein, wherein the treatment comprises        administering to the subject an amount of        (+)-α-dihydrotetrabenazine succinate corresponding to between        0.02 mg/kg and 0.2 mg/kg of (+)-α-dihydrotetrabenazine free base        per day, provided that the total amount of        (+)-α-dihydrotetrabenazine succinate administered per day is in        the range from 0.5 mg to 20 mg (e.g. 1 mg to 20 mg).    -   (+)-α-dihydrotetrabenazine succinate for use, a method or a use        as described herein, wherein the treatment comprises        administering to the subject an amount of        (+)-α-dihydrotetrabenazine succinate corresponding to between        0.03 mg/kg and 0.2 mg/kg of (+)-α-dihydrotetrabenazine free        base, provided that the total amount of        (+)-α-dihydrotetrabenazine succinate administered per day is in        the range from 0.5 mg to 20 mg (e.g. 1 mg to 20 mg).    -   (+)-α-dihydrotetrabenazine succinate for use, a method or a use        as described herein, wherein the treatment comprises        administering to the subject an amount of        (+)-α-dihydrotetrabenazine succinate corresponding to between        0.04 mg/kg and 0.2 mg/kg of (+)-α-dihydrotetrabenazine free        base, provided that the total amount of        (+)-α-dihydrotetrabenazine succinate administered per day is in        the range from 0.5 mg to 20 mg (e.g. 1 mg to 20 mg).    -   (+)-α-dihydrotetrabenazine succinate for use, a method or a use        as described herein, wherein the treatment comprises        administering to the subject an amount of        (+)-α-dihydrotetrabenazine succinate corresponding to between        0.05 mg/kg and 0.2 mg/kg of (+)-α-dihydrotetrabenazine free        base, provided that the total amount of        (+)-α-dihydrotetrabenazine free base administered per day is in        the range from 0.5 mg to 20 mg (e.g. 1 mg to 20 mg).    -   (+)-α-dihydrotetrabenazine succinate for use, a method or a use        as described herein, wherein the treatment comprises        administering to the subject an amount of        (+)-α-dihydrotetrabenazine succinate corresponding to between        0.02 mg/kg and 0.1 mg/kg of (+)-α-dihydrotetrabenazine free base        per day, provided that the total amount of        (+)-α-dihydrotetrabenazine succinate administered per day is in        the range from 0.5 mg to 20 mg (e.g. 1 mg to 20 mg).    -   (+)-α-dihydrotetrabenazine succinate for use, a method or a use        as described herein, wherein the treatment comprises        administering to the subject an amount of        (+)-α-dihydrotetrabenazine succinate corresponding to between        0.03 mg/kg and 0.1 mg/kg of (+)-α-dihydrotetrabenazine free        base, provided that the total amount of        (+)-α-dihydrotetrabenazine succinate administered per day is in        the range from 0.5 mg to 20 mg (e.g. 1 mg to 20 mg).    -   (+)-α-dihydrotetrabenazine succinate for use, a method or a use        as described herein, wherein the treatment comprises        administering to the subject an amount of        (+)-α-dihydrotetrabenazine succinate corresponding to between        0.04 mg/kg and 0.1 mg/kg of (+)-α-dihydrotetrabenazine free        base, provided that the total amount of        (+)-α-dihydrotetrabenazine succinate administered per day is in        the range from 0.5 mg to 20 mg (e.g. 1 mg to 20 mg).    -   (+)-α-dihydrotetrabenazine succinate for use, a method or a use        as described herein, wherein the treatment comprises        administering to the subject an amount of        (+)-α-dihydrotetrabenazine succinate corresponding to between        0.05 mg/kg and 0.1 mg/kg of (+)-α-dihydrotetrabenazine free        base, provided that the total amount of        (+)-α-dihydrotetrabenazine succinate administered per day is in        the range from 0.5 mg to 20 mg (e.g. 1 mg to 20 mg).    -   (+)-α-dihydrotetrabenazine succinate for use, a method or a use        as described herein, wherein the use or method comprises        administering to the subject an effective amount of        (+)-α-dihydrotetrabenazine succinate wherein:    -   (i) when the subject has a weight of 30 kg to 50 kg, the said        effective amount is a daily amount of (+)-α-dihydrotetrabenazine        or a pharmaceutically acceptable salt thereof corresponding to        from 2 mg to 7.5 mg of (+)-α-dihydrotetrabenazine free base;    -   (ii) when the subject has a weight of 50 kg to 75 kg, the said        effective amount is a daily amount of (+)-α-dihydrotetrabenazine        or a pharmaceutically acceptable salt thereof corresponding to        from 5 mg to 10 mg of (+)-α-dihydrotetrabenazine free base;    -   (iii) when the subject has a weight of 75 kg to 95 kg, the said        effective amount is a daily amount of (+)-α-dihydrotetrabenazine        or a pharmaceutically acceptable salt thereof corresponding to        from 7.5 mg to 15 mg of (+)-α-dihydrotetrabenazine free base; or    -   (iv) when the subject has a weight of greater than 95 kg, the        said effective amount is a daily amount of        (+)-α-dihydrotetrabenazine or a pharmaceutically acceptable salt        thereof corresponding to from 15 mg to 20 mg of        (+)-α-dihydrotetrabenazine free base the amount of        (+)-α-dihydrotetrabenazine administered per day is from 15 mg to        20 mg.

The present inventors have found that plasma levels of(+)-α-dihydrotetrabenazine required for effective treatment ofhyperkinetic movement disorders can be considerably lower than theplasma levels achieved by administration of Valbenazine as described inWO 2015/171802.

Accordingly, in a further aspect, the invention provides:

-   -   (+)-α-dihydrotetrabenazine succinate, or a pharmaceutically        acceptable salt thereof, for use in a method of treatment of a        movement disorder; or    -   A method of treatment of a movement disorder in a subject in        need thereof (e.g. a mammalian subject such as a human); or    -   The use of (+)-α-dihydrotetrabenazine succinate for the        manufacture of a medicament for the treatment of a movement        disorder        wherein the treatment comprises administering to a subject a        therapeutically effective amount of the        (+)-α-dihydrotetrabenazine succinate in an amount sufficient to        achieve an average blood plasma C_(avg) concentration of        (+)-α-dihydrotetrabenazine free base, where measured over a        period of three hours, in the range from 2 ng/ml to 15 ng/ml.

In one embodiment, the invention provides:

-   -   (+)-α-dihydrotetrabenazine succinate for use in a method of        treatment of a movement; or    -   A method of treatment of a movement disorder in a subject in        need thereof (e.g. a mammalian subject such as a human); or    -   The use of (+)-α-dihydrotetrabenazine succinate for the        manufacture of a medicament for the treatment of a movement        disorder;        wherein the treatment comprises administering to a subject a        therapeutically effective amount of the        (+)-α-dihydrotetrabenazine succinate in an amount sufficient to        achieve an average blood plasma C_(avg) concentration of        (+)-α-dihydrotetrabenazine free base, when measured over a        period of three hours, in the range from 3 ng/ml to 15 ng/ml.

Complete blocking of the VMAT2 proteins is considered undesirable asthis can lead to unwanted side effects, such as Parkinsonism. Thepresent invention provides plasma levels of (+)-α-dihydrotetrabenazinethat are sufficient to give effective treatment of movement disordersbut do not block the VMAT2 proteins to an extent that causesParkinsonism and similar side effects. The levels of VMAT2 blocking canbe determined by competitive binding studies using Positron EmissionTomography (PET). By co-administering a radioactive ligand with thecompound of interest at various concentrations, the proportion ofbinding sites occupied can be determined (see for example, Matthews etal., “Positron emission tomography molecular imaging for drugdevelopment”, Br. J. Clin. Pharmacol., 73:2, 175-186). Accordingly, theinvention also provides:

-   -   (+)-α-dihydrotetrabenazine succinate for use in a method for the        treatment of a movement disorder, wherein the treatment        comprises administering to a subject an amount of        (+)-α-dihydrotetrabenazine succinate sufficient to cause a level        of blocking of up to 90% of the VMAT2 proteins in the subject.    -   A method of treatment of a movement disorder in a subject in        need thereof (e.g. a mammalian subject such as a human), which        treatment comprises administering to the subject an amount of        (+)-α-dihydrotetrabenazine succinate sufficient to cause a level        of blocking of up to 90% of the VMAT2 proteins in the subject.    -   The use of (+)-α-dihydrotetrabenazine succinate for the        manufacture of a medicament for the treatment of a movement        disorder, which treatment comprises administering to the subject        an amount of (+)-α-dihydrotetrabenazine succinate sufficient to        cause a level of blocking of up to 90% of the VMAT2 proteins in        the subject.

In further embodiments, there is provided:

-   -   (+)-α-dihydrotetrabenazine succinate for use, a method or a use        as described herein, wherein the treatment comprises        administering to the subject an amount of        (+)-α-dihydrotetrabenazine succinate sufficient to cause a level        of blocking of up to 85% of the VMAT2 proteins in the subject.    -   (+)-α-dihydrotetrabenazine succinate for use, a method or a use        as described herein, wherein the treatment comprises        administering to the subject an amount of        (+)-α-dihydrotetrabenazine succinate sufficient to cause a level        of blocking of up to 80% of the VMAT2 proteins in the subject.    -   (+)-α-dihydrotetrabenazine succinate for use, a method or a use        as described herein, wherein the treatment comprises        administering to the subject an amount of        (+)-α-dihydrotetrabenazine succinate sufficient to cause a level        of blocking of up to 75% of the VMAT2 proteins in the subject.    -   (+)-α-dihydrotetrabenazine succinate for use, a method or a use        as described herein, wherein the treatment comprises        administering to the subject an amount of        (+)-α-dihydrotetrabenazine succinate sufficient to cause a level        of blocking of up to 70% of the VMAT2 proteins in the subject.    -   (+)-α-dihydrotetrabenazine succinate for use, a method or a use        as described herein, wherein the treatment comprises        administering to the subject an amount of        (+)-α-dihydrotetrabenazine succinate sufficient to cause a level        of blocking of from 25% to 85% of the VMAT2 proteins in the        subject.    -   (+)-α-dihydrotetrabenazine succinate for use, a method or a use        as described herein, wherein the treatment comprises        administering to the subject an amount of        (+)-α-dihydrotetrabenazine succinate sufficient to cause a level        of blocking of from 30% to 80% of the VMAT2 proteins in the        subject.    -   (+)-α-dihydrotetrabenazine succinate for use, a method or a use        as described herein, wherein the treatment comprises        administering to the subject an amount of        (+)-α-dihydrotetrabenazine succinate sufficient to cause a level        of blocking of from 35% to 75% of the VMAT2 proteins in the        subject.    -   (+)-α-dihydrotetrabenazine succinate for use, a method or a use        as described herein, wherein the treatment comprises        administering to the subject an amount of        (+)-α-dihydrotetrabenazine succinate sufficient to cause a level        of blocking of from 35% to 70% of the VMAT2 proteins in the        subject.    -   (+)-α-dihydrotetrabenazine succinate for use, a method or a use        as described herein, wherein the treatment comprises        administering to the subject an amount of        (+)-α-dihydrotetrabenazine succinate sufficient to cause a level        of blocking of from 40% to 75% of the VMAT2 proteins in the        subject.    -   (+)-α-dihydrotetrabenazine succinate for use, a method or a use        as described herein, wherein the treatment comprises        administering to the subject in need thereof, wherein the method        comprising administering to a subject an amount of        (+)-α-dihydrotetrabenazine succinate sufficient to cause a level        of blocking of from 45% to 75% of the VMAT2 proteins in the        subject.    -   (+)-α-dihydrotetrabenazine succinate for use, a method or a use        as described herein, wherein the treatment comprises        administering to the subject in need thereof, wherein the method        comprising administering to a subject an amount of        (+)-α-dihydrotetrabenazine succinate sufficient to cause a level        of blocking of from 35% to 80% of the VMAT2 proteins in the        subject.    -   (+)-α-dihydrotetrabenazine succinate for use, a method or a use        as described herein, wherein the treatment comprises        administering to the subject in need thereof, wherein the method        comprising administering to a subject an amount of        (+)-α-dihydrotetrabenazine succinate sufficient to cause a level        of blocking of from 40% to 80% of the VMAT2 proteins in the        subject.    -   (+)-α-dihydrotetrabenazine succinate for use, a method or a use        as described herein, wherein the treatment comprises        administering to the subject an amount of        (+)-α-dihydrotetrabenazine succinate sufficient to cause a level        of blocking of from 45% to 80% of the VMAT2 proteins in the        subject.    -   (+)-α-dihydrotetrabenazine succinate for use, a method or a use        as described herein, wherein the treatment comprises        administering to the subject an amount of        (+)-α-dihydrotetrabenazine succinate sufficient to cause a level        of blocking of from 50% to 80% of the VMAT2 proteins in the        subject.    -   (+)-α-dihydrotetrabenazine succinate for use, a method or a use        as described herein, wherein the treatment comprises        administering to the subject an amount of        (+)-α-dihydrotetrabenazine succinate sufficient to cause a level        of blocking of from 50% to 85% of the VMAT2 proteins in the        subject.    -   (+)-α-dihydrotetrabenazine succinate for use, a method or a use        as described herein, wherein the treatment comprises        administering to the subject an amount of        (+)-α-dihydrotetrabenazine succinate sufficient to cause a level        of blocking of from 55% to 80% of the VMAT2 proteins in the        subject.    -   (+)-α-dihydrotetrabenazine succinate for use, a method or a use        as described herein, wherein the treatment comprises        administering to the subject an amount of        (+)-α-dihydrotetrabenazine succinate sufficient to cause a level        of blocking of VMAT2 proteins in the subject of between 30% and        70%.    -   (+)-α-dihydrotetrabenazine succinate for use, a method or a use        as described herein, wherein the treatment comprises        administering to the subject in need thereof, wherein the method        comprising administering to a subject an amount of        (+)-α-dihydrotetrabenazine succinate sufficient to cause a        blocking level of VMAT2 proteins in the subject of between 30%        and 65%.    -   (+)-α-dihydrotetrabenazine succinate for use, a method or a use        as described herein, wherein the treatment comprises        administering to the subject in need thereof, wherein the method        comprising administering to a subject an amount of        (+)-α-dihydrotetrabenazine succinate sufficient to cause a        blocking level of VMAT2 proteins in the subject of between 30%        and 60%.    -   (+)-α-dihydrotetrabenazine succinate for use, a method or a use        as described herein, wherein the treatment comprises        administering to the subject in need thereof, wherein the method        comprising administering to a subject an amount of        (+)-α-dihydrotetrabenazine succinate sufficient to cause a level        blocking of VMAT2 proteins in the subject of between 40% and        80%.    -   (+)-α-dihydrotetrabenazine succinate for use, a method or a use        as described herein, wherein the treatment comprises        administering to the subject in need thereof, wherein the method        comprising administering to a subject an amount of        (+)-α-dihydrotetrabenazine succinate sufficient to cause a level        of blocking of VMAT2 proteins in the subject of between 40% and        75%.    -   (+)-α-dihydrotetrabenazine succinate for use, a method or a use        as described herein, wherein the treatment comprises        administering to the subject in need thereof, wherein the method        comprising administering to a subject an amount of        (+)-α-dihydrotetrabenazine succinate sufficient to cause a level        of blocking of VMAT2 proteins in the subject of between 40% and        70%.    -   (+)-α-dihydrotetrabenazine succinate for use, a method or a use        as described herein, wherein the treatment comprises        administering to the subject in need thereof, wherein the method        comprising administering to a subject an amount of        (+)-α-dihydrotetrabenazine succinate sufficient to cause a level        of blocking of VMAT2 proteins in the subject of between 40% and        65%.    -   (+)-α-dihydrotetrabenazine succinate for use, a method or a use        as described herein, wherein the treatment comprises        administering to the subject in need thereof, wherein the method        comprising administering to a subject an amount of        (+)-α-dihydrotetrabenazine succinate sufficient to cause a level        of blocking of VMAT2 in the subject of between 40% and 60%.

In each of the foregoing aspects and embodiments of the invention, the(+)-α-dihydrotetrabenazine succinate is typically not administered incombination with a therapeutically effective amount of amantadine. Moreparticularly, in each of the foregoing aspects and embodiments of theinvention, the (+)-α-dihydrotetrabenazine or pharmaceutically acceptablesalt thereof is typically not administered in combination with anyamount of amantadine.

The movement disorder can be a hyperkinetic movement disorder such asHuntington's disease, hemiballismus, senile chorea, tic disorders,tardive dyskinesia, dystonia, myoclonus and Tourette's syndrome. In oneEmbodiment, the movement disorder is Tourette's syndrome. In anotherembodiment, the movement disorder is tardive dyskinesia. In anotherembodiment, the movement disorder is Huntington's disease.

The term “treatment” as used herein in the context of treating acondition or disorder, pertains generally to treatment and therapy inwhich some desired therapeutic effect is achieved, for example, theinhibition of the progress of the condition, and includes a reduction inthe rate of progress, a halt in the rate of progress, amelioration ofthe condition, diminishment or alleviation of at least one symptomassociated or caused by the condition being treated and cure of thecondition. When the hyperkinetic movement disorder being treated isTourette's Syndrome, treatment of the disorder may pertain to areduction of the incidence or severity of tics.

Isotopes

The (+)-α-dihydrotetrabenazine succinate may contain one or moreisotopic substitutions, and a reference to a particular element includeswithin its scope all isotopes of the element. For example, a referenceto hydrogen includes within its scope ¹H, ²H (D), and ³H (T). Similarly,references to carbon and oxygen include within their scope respectively¹¹C, ¹²C, ¹³C and ¹⁴C and ¹⁶O and ¹⁸O.

Typically, the (+)-α-dihydrotetrabenazine succinate of the inventiondoes not contain isotopes (such as ¹¹C or ³H) in amounts higher thantheir natural abundance.

In one embodiment, the percentage of the total hydrogen atoms in the(+)-α-dihydrotetrabenazine succinate that are deuterium atoms is lessthan 2%, more typically less than 1%, more usually less than 0.1%,preferably less than 0.05% and most preferably no more than 0.02%.

In an analogous manner, a reference to a particular functional groupalso includes within its scope isotopic variations, unless the contextindicates otherwise.

The isotopes may be radioactive or non-radioactive. In one embodiment ofthe invention, the (+)-α-dihydrotetrabenazine succinate contains noradioactive isotopes. Such compounds are preferred for therapeutic use.In another embodiment, however, the (+)-α-dihydrotetrabenazine succinatemay contain one or more radioisotopes. Compounds containing suchradioisotopes may be useful in a diagnostic context.

Solvates

(+)-α-Dihydrotetrabenazine succinate may form solvates.

Examples of solvates are solvates formed by the incorporation into thesolid state structure (e.g. crystal structure) of the compounds of theinvention of molecules of a non-toxic pharmaceutically acceptablesolvent (referred to below as the solvating solvent). Examples of suchsolvents include water, alcohols (such as ethanol, isopropanol andbutanol) and dimethylsulphoxide. Solvates can be prepared byrecrystallising the compounds of the invention with a solvent or mixtureof solvents containing the solvating solvent. Whether or not a solvatehas been formed in any given instance can be determined by subjectingcrystals of the compound to analysis using well known and standardtechniques such as thermogravimetric analysis (TGE), differentialscanning calorimetry (DSC) and X-ray crystallography.

The solvates can be stoichiometric or non-stoichiometric solvates.

Particular solvates are hydrates, and particular examples of hydratesinclude hemihydrates, monohydrates and dihydrates.

For a more detailed discussion of solvates and the methods used to makeand characterise them, see Bryn et al., Solid-State Chemistry of Drugs,Second Edition, published by SSCI, Inc of West Lafayette, Ind., USA,1999, ISBN 0-967-06710-3.

Alternatively, rather than existing as a hydrate, the(+)α-dihydrotetrabenazine succinate of the invention may be anhydrous.Therefore, in another embodiment, the (+)-α-dihydrotetrabenazinesuccinate is in an anhydrous form.

Methods for the Preparation of Dihydrotetrabenazine Succinate Salts

(+)-α-Dihydrotetrabenazine (compound of formula (I)) can be preparedfrom tetrabenazine according to the synthetic route shown in Scheme 1.

Racemic tetrabenazine(3-isobutyl-9,10-dimethyoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1,a]isoquinolin-2-one)containing the RR and SS isomers of tetrabenazine is reduced with sodiumborohydride to afford a mixture of four dihydrotetrabenazine isomers ofwhich a racemic mixture of the α-dihydrotetrabenazines (RRR and SSSisomers) constitutes the major product and a racemic mixture of theβ-dihydrotetrabenazines (the SRR and RSS isomers) constitutes a minorproduct. The β-dihydrotetrabenazines can be removed during an initialpurification procedure, for example by chromatography orrecrystallization and then the racemic α-dihydrotetrabenazines resolved(e.g. by recrystallisation with di-p-toluoyl-L-tartaric acid or(R)-(−)-camphorsulfonic acid or by chiral chromatography), to afford(+)-α-dihydrotetrabenazine (I) ((2R, 3R,11bR)-3-isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-2H-pyrido[2,1,a]isoquinolin-2-ol).

(+)-α-Dihydrotetrabenazine can also be prepared according to Yao et al.,“Preparation and evaluation of tetrabenazine enantiomers and all eightstereoisomers of dihydrotetrabenazine as VMAT2 inhibitors”, Eur. J. Med.Chem., (2011), 46, pp. 1841-1848.

The (+)-α-dihydrotetrabenazine succinate salt can then be prepared byreacting the (+)-α-DHTBZ free base with succinic acid. The reaction istypically carried out in the presence of a solvent.

Accordingly, in a further aspect of the invention, there is provided aprocess for preparing a (+)-α-dihydrotetrabenazine succinate salt of theinvention, which process comprises mixing (+)-α-dihydrotetrabenazinefree base of the formula (I):

with succinic acid together with a solvent, allowing formation of thesalt to take place, and isolating the (+)-α-dihydrotetrabenazinesuccinate salt.

In one embodiment, the process for preparing (+)-alpha-DHTBZ succinatesalt comprises reacting the (+)-alpha-DHTBZ free base of Formula (II)and succinic acid together with a solvent to form a reaction mixture andthen stirring the reaction mixture for a period of at least one hour,more typically at least 2 hours, or at least 4 hours, or at least 12hours, for example at least 1 day.

The solvent may be a single solvent or may comprise a mixture ofsolvents. Generally the solvent will consist of or contain at least onepolar aprotic solvent, examples being acetone and ethyl acetate.

In one embodiment, the solvent is selected from acetone, ethyl acetateand mixtures thereof.

In a particular embodiment, the solvent is acetone.

A preferred method of preparing (+)-α-dihydrotetrabenazine succinatesalt comprises forming a slurry from (+)-α-dihydrotetrabenazine,succinic acid (e.g. at room temperature) and a non-aqueous solvent andstirring the slurry for a time period long enough to permit formation ofthe succinate salt. The time period is typically at least four hours,more usually at least six hours, or at least twelve hours, and inparticular at least eighteen hours. A particular non-aqueous solvent foruse in this method is acetone.

Pharmaceutical Formulations and Methods of Treatment

The pharmaceutical compositions of the invention can be in any formsuitable for oral, parenteral, topical, intranasal, intrabronchial,ophthalmic, otic, rectal, intra-vaginal, or transdermal administration.Where the compositions are intended for parenteral administration, theycan be formulated for intravenous, intramuscular, intraperitoneal,subcutaneous administration or for direct delivery into a target organor tissue by injection, infusion or other means of delivery.

Pharmaceutical dosage forms suitable for oral administration includetablets, capsules, caplets, pills, lozenges, syrups, solutions, sprays,powders, granules, elixirs and suspensions, sublingual tablets, sprays,wafers or patches and buccal patches.

Pharmaceutical compositions containing (+)-α-dihydrotetrabenazinesuccinate can be formulated in accordance with known techniques, see forexample, Remington's Pharmaceutical Sciences, Mack Publishing Company,Easton, Pa., USA.

Thus, tablet compositions can contain a unit dosage of active compoundtogether with an inert diluent or carrier such as a sugar or sugaralcohol, e.g.; lactose, sucrose, sorbitol or mannitol; and/or anon-sugar derived diluent such as sodium carbonate, calcium phosphate,talc, calcium carbonate, or a cellulose or derivative thereof such asmethyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, andstarches such as corn starch. Tablets may also contain such standardingredients as binding and granulating agents such aspolyvinylpyrrolidone, disintegrants (e.g. swellable crosslinked polymerssuch as crosslinked carboxymethylcellulose), lubricating agents (e.g.stearates), preservatives (e.g. parabens), antioxidants (e.g. BHT),buffering agents (for example phosphate or citrate buffers), andeffervescent agents such as citrate/bicarbonate mixtures. Suchexcipients are well known and do not need to be discussed in detailhere.

Capsule formulations may be of the hard gelatin or soft gelatin varietyand can contain the active component in solid, semi-solid, or liquidform. Gelatin capsules can be formed from animal gelatin or synthetic orplant derived equivalents thereof.

The solid dosage forms (e.g.; tablets, capsules etc.) can be coated orun-coated, but typically have a coating, for example a protective filmcoating (e.g. a wax or varnish) or a release controlling coating. Thecoating (e.g. a Eudragit™ type polymer) can be designed to release theactive component at a desired location within the gastro-intestinaltract. Thus, the coating can be selected so as to degrade under certainpH conditions within the gastrointestinal tract, thereby selectivelyrelease the compound in the stomach or in the ileum or duodenum.

Instead of, or in addition to, a coating, the drug can be presented in asolid matrix comprising a release controlling agent, for example arelease delaying agent which may be adapted to selectively release thecompound under conditions of varying acidity or alkalinity in thegastrointestinal tract. Alternatively, the matrix material or releaseretarding coating can take the form of an erodible polymer (e.g. amaleic anhydride polymer) which is substantially continuously eroded asthe dosage form passes through the gastrointestinal tract.

Compositions for topical use include ointments, creams, sprays, patches,gels, liquid drops and inserts (for example intraocular inserts). Suchcompositions can be formulated in accordance with known methods.

Compositions for parenteral administration are typically presented assterile aqueous or oily solutions or fine suspensions, or may beprovided in finely divided sterile powder form for making upextemporaneously with sterile water for injection. Examples offormulations for rectal or intra-vaginal administration includepessaries and suppositories which may be, for example, formed from ashaped mouldable or waxy material containing the active compound.

Compositions for administration by inhalation may take the form ofinhalable powder compositions or liquid or powder sprays, and can beadministrated in standard form using powder inhaler devices or aerosoldispensing devices. Such devices are well known. For administration byinhalation, the powdered formulations typically comprise the activecompound together with an inert solid powdered diluent such as lactose.

Compositions for administration by inhalation may take the form ofinhalable powder compositions or liquid or powder sprays, and can beadministrated in standard form using powder inhaler devices or aerosoldispensing devices. Such devices are well known. For administration byinhalation, the powdered formulations typically comprise the activecompound together with an inert solid powdered diluent such as lactose.

Particular pharmaceutical compositions of the invention are compositionsselected from:

-   -   Sublingual compositions;    -   Intranasal;    -   Pellets or tablets formulated to provide release kinetics        corresponding to zero order release of the active compound;    -   Pellets or tablets formulated to provide first fast release        followed by constant rate release (zero order) of the active        compound;    -   Pellets or tablets formulated to provide a mixture of first        order and zero order release of the active compound; and    -   Pellets or tablets formulated to provide a combination of zero        order and first order release of the active compound; and        optionally a further order of release of the active compound        selected from second, third and fourth orders of release and        combinations thereof.

Pellets and tablets formulated to provide release kinetics of the typesdefined above can be prepared according to methods well known theskilled person; for example as described in Remington's PharmaceuticalSciences (idem) and “Remington—The Science and Practice of Pharmacy,21^(st) edition, 2006, ISBN 0-7817-4673-6.

The compounds of the invention will generally be presented in unitdosage form and, as such, will typically contain an amount of compoundsufficient to provide a desired level of biological activity. Suchamounts are set out above.

The active compound will be administered to a subject (patient) in needthereof (for example a human or animal patient) in an amount sufficientto achieve the desired therapeutic effect, as described above.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a stackplot showing the XRPD patterns for various batches of(+)-α-dihydrotetrabenazine succinate salt together with the XRPD patternfor succinic acid and the XRPD pattern for a solid obtained from afailed attempt to produce the succinate salt.

FIG. 2 shows the ¹H NMR spectrum (recorded using DMSO as the solvent)for the (+)-α-dihydrotetrabenazine succinate salt.

FIG. 3 shows a DSC thermogram for the (+)-α-dihydrotetrabenazinesuccinate salt.

FIG. 4 shows a TGA thermogram for the (+)-α-dihydrotetrabenazinesuccinate salt.

FIG. 5 is a moisture-sorption plot for the (+)-α-dihydrotetrabenazinesuccinate salt.

FIG. 6 shows the average total distance travelled by rats when treatedwith vehicle (with or without amphetamine induction) and(+)-α-dihydrotetrabenazine at doses of 0.5, 1, 1.5 and 2 mg/kg andrisperidone at a dose of 1 mg/kg in amphetamine-induced rats, asdescribed in Example 4, Study 1 below.

FIG. 7 shows the average total stereotypic behaviour by rats whentreated with vehicle (with or without amphetamine induction) and(+)-α-dihydrotetrabenazine at doses of 0.5, 1, 1.5 and 2 mg/kg andrisperidone at a dose of 1 mg/kg in amphetamine-induced rats, asdescribed in Example 4, Study 1 below.

FIG. 8 shows the average total distance travelled by rats when treatedwith vehicle (with or without amphetamine induction) and(+)-α-dihydrotetrabenazine at doses of 0.1 mg/kg and 0.25 mg/kg andrisperidone at a dose of 1 mg/kg in amphetamine-induced rats, asdescribed in Example 4, Study 2 below.

FIG. 9 shows the average total stereotypic behaviour by rats whentreated with vehicle (with or without amphetamine induction) and(+)-α-dihydrotetrabenazine at doses of 0.1 mg/kg and 0.25 mg/kg andrisperidone at a dose of 1 mg/kg in amphetamine-induced rats, asdescribed in Example 4, Study 2 below.

FIG. 10 shows the average total distance travelled by rats when treatedwith vehicle and (+)-α-dihydrotetrabenazine at a dose of 2.5 mg/kg or 5mg/kg and risperidone at a dose of 1 mg/kg in rats without amphetamineinduction, as described in Example 4, Study 3 below.

FIG. 11 shows the average total stereotypic behaviour by rats whentreated with vehicle and (+)-α-dihydrotetrabenazine at a dose of 2.5mg/kg or 5 mg/kg and risperidone at a dose of 1 mg/kg in rats withoutamphetamine induction, as described in Example 4, Study 3 below.

EXAMPLES

The following non-limiting examples illustrate the synthesis andproperties of salts of (+)-alpha-dihydrotetrabenazine.

Materials and Methods

X-ray powder diffraction (XRPD) studies were carried out using aCubiX-Pro apparatus. XRPD analysis was carried out on the sample “asis”. Each sample was placed on a Si zero-return ultra-micro sampleholder. Analysis was performed using a 10 mm irradiated width, and thefollowing parameters were set within the hardware/software:

X-ray tube: Cu KV, 45 kV, 40 mA

Detector: X'Celerator

ASS primary slit: Fixed 1°Divergence slit (Prog): Automatic—5 mm irradiated lengthSoller slits: 0.02 radianScatter slit (PASS): Automatic—5 mm observed lengthScan range: 3.0-45.0°Scan mode: ContinuousStep size: 0.02°Time per step: 10 secondsActive length: 2.54°

¹H NMR studies were carried out using a Bruker 500 MHz AVANCE apparatus.The sample was dissolved in DMSO-d₆ with 0.05% tetramethylsilane (TMS)as an internal reference. the ¹H NMR spectrum was recorded at 500 MHzusing a 55 mm broadband (¹H-X) Z gradient probe. A 30 degree pulse with20 ppm spectral width, 1.0 second repetition rate, and 32 transientswere used in acquiring the spectrum.

Differential scanning calorimetry (DSC) was carried out on the sample“as is” using a Mettler DSC1 instrument. The sample was weighed I analuminium pan, covered with a pierced lid, and then crimped and analysedfrom 30-300° C. at 10° C./minute.

Thermal gravimetric analysis was performed on the sample “as is” using aMettler 851^(θ) TGA instrument. The sample was weighed in an aluminacrucible and analysed from 30-300° C. at 10° C./minute.

Moisture-sorption analysis was carried out using a Hiden IGA Sorpmoisture-sorption analyser. The analysis was carried out by firstholding the sample at 40% relative humidity and 25° C. until anequilibrium weight was reached, or for a maximum of four hours. Thesample was then subjected to an isothermal (at 25° C.) adsorption scanfrom 40 to 90% relative humidity in steps of 10%. The sample was allowedto equilibrate to an asymptotic weight at each point for a maximum offour hours. Following adsorption, a desorption scan from 85 to 5%relative humidity (at 25° C.) was run in steps of 10%, again allowingfor a maximum of four hours to an asymptotic weight. An adsorption scanwas then performed from 0 to 40% relative humidity inn steps of 10%. Thesample was dried for two hours at 60° C. and 0% relative humidity, andthe resulting solid was analysed by XRPD.

The aqueous solubilities of salts were measured by an equilibrium methodin which an amount of the salt was weighed into a 2 ml vial equippedwith a magnetic stirrer bar and water added. In cases where completedissolution was observed, more material was added until the sample wasexhausted. The slurry was then stirred for seven days before isolatingthe solids by centrifuge-filtration. The solids were analysed by XRPDand the filtrates were analysed by HPLC to determine the amount of(+)-alpha-dihydrotetrabenazine salt in solution. The solubilities werecalculated against a calibration curve established for a(+)-alpha-dihydrotetrabenazine sample of known concentration.

The HPLC system used was as follows:

System: Agilent 100 Series HPLC Column: Phenomenex (Prodigy ODS3, 5 μm,4.6 × 250 mm Mobile phase A: 10 mM ammonium acetate (pH 8.0) Mobilephase B: 9:1 (v/v) acetonitrile/10 mM 10 mM ammonium acetate (pH 8.0)Diluent: 1:1 (v/v) acetonitrile/water DAD detector: 235 nm Injectionvolume: 10 μL (2-12 μL for calibration curve) Flow rate: 1.0 mL/minuteColumn temperature: 25° Auto sampler temperature: Ambient Run time: 40.1minutes Post-run time: 5 minutes Gradient: Time (minutes) % MP A % MP B 0 90 10 30 30 70 35 10 90 40 10 90 40.1 90 10

Example 1

An Investigation into the Ability of 2R,3R,11bR-Dihydrotetrabenazine toForm Salts

Experiments were carried out to assess the ability of(+)-α-dihydrotetrabenazine to form acid addition salts from a variety ofmineral and organic acids. More specifically, attempts were made toprepare salts of (+)-α-dihydrotetrabenazine with hydrochloric acid,sulphuric acid, phosphoric acid, L-tartaric acid, citric acid, L-malicacid, adipic acid, methanesulphonic acid, succinic acid,benzenesulphonic acid and naphthalenesulphonic acid. In a firstexperiment, solutions of (+)-α-dihydrotetrabenazine (32 mg/ml) in eitherethyl acetate or acetone were prepared and divided into 1 ml aliquots,each of which was introduced into a 4 ml glass vial equipped with astirrer bar and the temperature of the solution maintained at 50° C.using a J-KEM heating block. An acid (1.05 molar equivalents) dissolvedin dioxane or aqueous dioxane was then added in a dropwise manner.Following addition of the acid, the resulting mixture was graduallycooled to room temperature at a cooling rate of 20° C./hour. Oncecooled, the solutions were stirred overnight. Any solids that had formedafter this time were separated by centrifuge filtration. Solutions thatremained clear were evaporated down to give a residue. In the greatmajority of cases, the residues were oils. Solids, whether obtained byfiltration or by evaporation of solvent, were examined for crystallinityusing XRPD. In this experiment, crystalline hydrochloric acid salts wereobtained from both ethyl acetate and acetone solutions of(+)-α-dihydrotetrabenazine, and a crystalline benzenesulphonate salt wasobtained from an ethyl acetate solution of the (+)-α-DHTBZ. An amorphousphosphoric acid salt was obtained from both ethyl acetate and acetonesolutions. The succinic acid-containing vial deposited a solid which,when filtered and analysed by XRPD, proved to be succinic acid ratherthan a succinate salt of (+)-α-dihydrotetrabenazine

In a second experiment, oils and amorphous solids obtained in the firstexperiment were mixed with 0.5 ml of acetonitrile and stirred for threedays at room temperature before filtering off any solids or evaporatingclear solutions to give either a solid or oil residue. All solidsobtained in this second experiment were tested for crystallinity byXRPD.

In this second experiment, crystalline sulphate and partly crystallinenaphthalene-2-sulphonic acid salts were obtained along with a mostlyamorphous phosphoric acid salt. As in the first experiment, the succinicacid-containing vial deposited a solid which, when filtered and analysedby XRPD (see FIG. 1 plot ZEN-E-6-7a), provided to be succinic acid (seeFIG. 1 plot Succinic acid) rather than a succinate salt of(+)-α-dihydrotetrabenazine.

In a third experiment, to each of the vials from the second experimentthat contained L-tartaric acid, succinic acid, citric acid, L-malicacid, adipic acid and methanesulphonic acid was added 0.5 ml of ethylacetate and the resulting mixtures were stirred for ten days at roomtemperatures. At the end of this period, any slurries were eitherfiltered or subjected to decanting and any clear solutions wereevaporated to dryness under a gentle stream of nitrogen. This experimentproduced crystalline (+)-α-dihydrotetrabenazine succinate salt which wasfiltered off, dried under vacuum and then subjected to XRPD analysis toconfirm its crystallinity (see FIG. 1 plot ZEN-E-6-7b).

The foregoing experiments demonstrate the difficulty in forming acidaddition salts of (+)-α-dihydrotetrabenazine. Thus, of the freebase/acid combinations tested, only succinic acid, hydrochloric acid,sulphuric acid, benzenesulphonic acid, and naphthalene-2-sulphonic acidsformed crystalline salts with (+)-α-dihydrotetrabenazine. Thenaphthalene-2-sulphonic acid salt was, however, gummy, brown andsomewhat difficult to handle. A solid material was obtained by reactionwith phosphoric acid but this was amorphous.

Example 2 Further Characterisation of (+)-α-Dihydrotetrabenazine Salts

Based on the studies described in Example 1, the succinic acid,hydrochloric acid, sulphuric acid and benzenesulphonic acid salts wereselected for further characterisation.

2A. Hydrochloride Salt Form A

(+)-α-Dihydrotetrabenazine free base (30 mg) was dissolved in acetone (1ml) at 50° C. in an 8 ml vial and 0.225 ml of a 0.5M solution ofhydrochloric acid in either water or a 1:7 dioxane:water mixture(corresponding to 1.1 molar equivalents relative to the free base) wasadded dropwise with stirring to the vial. The vial was cooled slowly toambient temperature and stirred overnight. The resulting solution wasthen evaporated to dryness under a gentle stream of nitrogen.Acetonitrile (0.5 ml) was added and the mixture was stirred to form aslurry. After three days of stirring, the resulting solids were isolatedby centrifuge-filtration and dried at ambient temperature under reducedpressure to give (+)-α-dihydrotetrabenazine hydrochloride crystallineform A, the crystallinity of which was confirmed by XRPD analysis.

The ¹H NMR spectrum of (+)-α-dihydrotetrabenazine hydrochloridecrystalline form A is consistent with that of the free base. The saltratio was found to be 0.95:1. Crystalline HCl salt form A was subjectedto DSC analysis and showed endotherms at 245° C. and 283° C. No weightloss was observed by TGA analysis. Thus, the HCl salt form A has goodthermal stability.

The equilibrium solubility of HCl salt form A was determined by HPLC andwas found to be 203 mg/mol.

2B. Hydrochloride Salt Form B

When HCl salt form A was stirred in an aqueous slurry for one weekconversion to a different (by XRPD) crystalline form (salt form B) tookplace. Salt form B was found to have a salt ratio of 0.83:1. DSCanalysis showed endotherms at 96° C., 114° C. and 246° C. and a singleexotherm at 165° C. TGA analysis showed a 1.2% loss in weight. The dataindicated that salt form B is a hydrate. This salt form was notcharacterised further due to its undesirable thermal behaviour.

2C. Sulphate Salt

(+)-α-Dihydrotetrabenazine free base (300 mg) was dissolved in ethylacetate (10 ml) at 50° C. and 2.190 ml of a 0.50M solution of sulphuricacid in 3:1 dioxane:water (corresponding to 1.1 molar equivalents) wasadded dropwise with stirring to the solution of free base. The solutionwas then cooled slowly (at a rate of 20° C. per hour) to roomtemperature and stirred overnight. The clear solution was thenevaporated to dryness under a gentle stream of nitrogen. Acetonitrile (5ml) was added to the residue and the resulting slurry was stirred forthree days. The solids were then isolated by centrifuge filtration anddried at ambient temperature under reduced pressure to give the sulphatesalt as a crystalline solid, the crystallinity of which was confirmed byXRPD.

DSC analysis of the sulphate salt showed endotherms at 209° C. and 279°C. and a single exotherm at 223° C. TGA analysis showed a 3.7% weightloss.

The salt ratio for the sulphate salt was found to vary from batch tobatch. In one batch, a salt ratio of 0.67:1 was obtained while inanother batch the salt had a salt ratio of only 0.27:1. Because of thevariability of the salt ratio, the sulphate salt was not characterisedfurther.

2D. Benzenesulphonate Salt

(+)-α-Dihydrotetrabenazine free base (300 mg) was dissolved in acetone(10 ml) at 50° C. and 2.10 ml of a 0.50M solution of benzenesulphonicacid in dioxane (corresponding to 1.1 molar equivalents) was addeddropwise with stirring to the solution of free base. The solution wasthen cooled slowly (at a rate of 20° C. per hour) to room temperatureand stirred overnight. The resulting solids were then isolated bycentrifuge filtration and dried at ambient temperature under reducedpressure to give the benzenesulphonate salt as a crystalline solid, thecrystallinity of which was confirmed by XRPD.

The salt ratio was analysed by NMR and the 1H NMR spectrum was found tobe consistent with was found to be 1.1:1. DSC analysis showed a singleendotherm at 249° C. No weight loss was observed by TGA analysis. Ingravimetric moisture-sorption studies, the salt was observed to beslightly hygroscopic, moisture uptake of 0.2 wt % being observed at 60%relative humidity and 1.7 wt % moisture uptake being observed at 90%relative humidity.

The benzenesulphonate salt remained unchanged (according to XRPDanalysis) after one week of stirring in a water, ethanol and ethylacetate slurry.

The equilibrium solubility of the benzenesulphonate salt was found to be2.20 mg/ml by HPLC studies.

2E. Preparation of (+)-α-Dihydrotetrabenazine Succinate Salt

(+)-α-Dihydrotetrabenazine free base (313 mg) and succinic acid (116 mg,1.0 Molar equivalent) were introduced in the solid state into a 20 mLvial equipped with a magnetic stirrer bar. Acetone (1.0 ml) was addedand the resulting slurry was stirred for 4 days at room temperaturebefore filtering to afford the (+)-α-dihydrotetrabenazine succinatesalt.

The succinate salt was characterised by X-Ray Powder Diffraction (XRPD),¹H NMR, Differential Scanning Calorimetry (DSC) and ThermogravimetricAnalysis (TGA).

The XRPD pattern for the salt is shown in FIG. 1 (see plotSUN-A-J-163(2)). The XRPD pattern illustrates that the salt iscrystalline.

The ¹H NMR spectrum (recorded using DMSO as the solvent) for the salt isshown in FIG. 2. The ¹H NMR spectrum confirms that the salt ratio is1.0:1; i.e. the salt contains one mole of the free base for each mole ofsuccinic acid.

The DSC thermogram for the salt is shown in FIG. 3. The thermogram showsendotherms at 150° C., 202° C. and 264° C.

The TGA thermogram for the salt is shown in FIG. 4. No weight loss wasobserved below 150° C.

Moisture-sorption analysis was carried out and the salt was found to beslightly hygroscopic. A moisture-sorption plot is shown in FIG. 5. Amoisture uptake of 0.6 weight % was observed at 60% relative humidityand a moisture uptake of 1.3 weight % was observed at 90% relativehumidity. After completion of the moisture sorption studies, the saltwas dried at 60° C. and 0% relative humidity and the XRPD pattern takenagain (see FIG. 1 SUN-A-J-163(2)). No change from the original XRPDpattern was observed.

The analytical data described above are consistent with the succinatesalt being an anhydrate.

An attempt was also made to form the hemi-succinate salt of(+)-α-dihydrotetrabenazine by mixing a solution of the free base inethyl acetate with 0.55 molar equivalents of succinic acid in 4:1dioxane:water at 50° C., cooling the mixture at a rate of 20° C. perhour to room temperature and then stirring overnight. The resultingsolution was evaporated to form an oil. Ethyl acetate was then added tothe oil and the mixture was stirred for four days at room temperature.The resulting slurry was filtered by centrifuge filtration and theisolated solids dried at room temperature overnight under reducedpressure. The dried solid was analysed by ¹H NMR and XRPD and wasidentified as the mono-salt rather than the hemi-salt. The XRPD patternis shown in FIG. 1 (see plot LYO-F-4(3)).

(+)-α-Dihydrotetrabenazine Salt Formation—Conclusions

The experiments described above demonstrate that the preparation ofsalts of (+)-α-dihydrotetrabenazine is not straightforward. Indeed, manyacids that are known to form stable acid addition salts with otherpharmacologically active compounds fail to form crystalline salts with(+)-α-dihydrotetrabenazine, or do so only with difficulty.

Of those crystalline salts that were prepared, the most water-solublesalt was the succinate salt which had a solubility (as measured by HPLC)in water of greater than 350 mg/ml. The succinate salt also had goodthermal stability and no evidence of polymorphism was found. Thesuccinate salt was the mono-salt (i.e. there is a 1:1 ratio offreebase:acid). An attempt to make the hemi-salt by using 0.55 molarequivalents of the acid failed and resulted in formation of themono-salt. The hydrochloride salt also had good aqueous solubility (203mg/ml) but exhibited undesirable polymorphism, with the more stable “A”crystalline form transforming to the less thermally stable “B”crystalline form when left in a aqueous slurry.

The sulphate salt suffered from variability in the salt ratio and, innone of the studies carried out, was a salt ratio characteristic ofeither a 1:1 salt or a hemi-salt obtained.

Finally, the benzenesulphonate salt, whilst showing good thermalstability and no apparent polymorphism, had undesirably low solubility(2.20 mg/ml compared to 0.127 mg/ml for the free base).

The most promising salt, from both a stability and solubilityperspective, was therefore the succinate salt. This salt could be formedin good yield simply by stirring a slurry of the free base and the acidin acetone for a prolonged period.

Biological Properties

In the following Examples 3, 4 and 5, the biological properties of(+)-α-dihydrotetrabenazine and (+)-α-dihydrotetrabenazine succinate saltare described.

Example 3

(+)-α-Dihydrotetrabenazine in amounts was administered by oral dosing tofive human volunteers. In four of the volunteers, blood sample weretaken at 30, 60, 120 and 180 minutes after drug administration. Bloodsamples were not taken from the fifth volunteer. At 60 minutes afterdrug administration, PET scans were initiated and these were stopped at120 minutes after drug administration.

The experiment was carried out at dosages of 7.5 mg, 15 mg and 22.5 mg.

Results

Table 1 shows the plasma concentrations in nanogrammes/ml of(+)-α-dihydrotetrabenazine in 4 human subjects, 0.5, 1, 1.5, 2 and 3hours after a dose of 7.5 mg, 15 mg and 22.5 mg. Table 2 shows the %VMAT2 blocking following administration of 7.5 mg, 15 mg and 22.5 mg of(+)-α-dihydrotetrabenazine in all five subjects.

TABLE 1 Subject # 1 2 3 4 5 Body Weight (kg) Dose (oral) Time (h) 112 76129 59 91  7.5 mg 0.5 BLQ 0.531 0.216 8.43 ND 1 0.94 13.7 4.35 15.0 ND1.5 2.39 10.8 6.91 20.7 ND 2 2.44 14.0 5.03 17.6 ND 3 3.01 22.2 6.9619.6 ND  15 mg 0.5 4.02 7.99 1.2 26.7 ND 1 11.1 22.8 14.3 53.8 ND 1.510.7 46.4 17.9 42.5 ND 2 10.2 35.7 12.0 53.3 ND 3 10.6 46.5 18.2 60.2 ND22.5 mg  0.5 9.61 5.23 9.04 ND ND 1 18.0 21.8 34.7 ND ND 1.5 16.8 36.229.8 ND ND 2 14.9 40.2 26.3 ND ND 3 13.2 51.8 17.3 ND ND BLQ—Below levelof quantitation, ND—Not done

TABLE 2 Subject # 1 2 3 4 5 Body Weight (kg) Dose (oral) 112 76 129 5991 7.5 mg 54 73 62 84 73  15 mg 73 83 69 89 79 22.5 mg  75 82 74 ND 82

Although in subjects with a lower body weight, higher(+)-α-dihydrotetrabenazine blood plasma concentrations were observed fora given dose, it can be seen that even in heavier individuals, at least50% % VMAT2 blocking was observed at doses as low as 7.5 mg and, inlighter individuals, significantly higher % VMAT2 binding was. It wasalso observed that during the period of PET scanning, average plasmalevels of less than 15 ng/ml gave rise to % VMAT2 binding of at least50%. The data demonstrate that very low doses of(+)-α-dihydrotetrabenazine resulting in plasma concentrations of lessthan 15 ng/ml can still give high levels of VMAT2 blocking.

Example 4—Comparison of the Effect of Dihydrotetrabenazines andRisperidone on Amphetamine-Induced Hyperlocomotion

Dopaminergic models for Tourette's syndrome use systemic or focaladministration of dopamine agonists such as amphetamine. After injectionwith amphetamine, a test animal expresses stereotypic behaviour. Inparticular, involvement of a dopaminergic system implicated inTourette's syndrome wild type mice and rats can be stimulated withamphetamine and the resulting hyperactivity and stereotypies can bereversed with dopamine antagonists such as risperidone and haloperidol(Tourette's syndrome—Animal Models for Screening, Charles RiverDiscovery Research Services, Finland).

Amphetamine produced a rise in extracellular concentrations of braindopamine and concomitant behavioural manifestations in the rat and otherspecies. At relatively low doses (1.2 ng/kg i.p.) amphetamine increaseslocomotor behaviour, ceases movement and gives way to a stationaryposture accompanied by highly repetitive rapid head movements. Thislatter non-locomotor phase of stimulation is referred to as focusedstereotypy. The stereotypy can last for over an hour and is usuallyfollowed by a period of locomotor stimulation (Schiorring 1971).

Administration of dopamine agonists (such as amphetamine) is known toinduce behavioural stereotypies and sensorimotor gating disruption.Also, dopaminergic, cholinergic (TANs) and HDC models (subsequent tostress and/or amphetamine injection) are known to show an increase instereotypic behaviours (Yaol et al 2016).

Amphetamine induced stereotype behaviour has also been evaluated as amodel for the movement disorder condition, tardive dyskinesia (seeRubovitis et al (1972)).

The atypical antipsychotic drug risperidone is commonly used for thetreatment of Tourette's syndrome and has been described (J. D. Walkup, AGuide to Tourette Syndrome Medications, Publ. 2008, The NationalTourette Syndrome Association, Inc.) as being probably the best atypicalantipsychotic for tic suppression with potentially less risk of motorside effects than haloperidol and fluphenazine.

Three studies were carried out to compare the effects ofdihydrotetrabenazines and risperidone on amphetamine-induced andnon-amphetamine-induced hyperlocomotion in rats, on the basis that, forthe reasons given above, locomotor studies are useful models forTourette's syndrome and other movement disorders.

Materials and Methods Equipment

Open field arena, Med Associates Inc.

Plastic syringes 1 ml, Terumo. Ref: SS-01T1

Animal feeding needle 15 G, Instech Solomon, Cat: 72-4446

Sartorius Mechatronics Scale A22101, Sartorius Weighting Technology,Germany

Needle 27 G Terumo Myjector, 0.5 ml, Ref: 8300010463

Plastic syringes 3 ml, Soft-Ject, Ref: 8300005761

BD Microtainer K2EDTA tubes Ref: 365975

Matrix 0.75 ml, Alphanum Tubes, Thermo Scientific, Ref: 4274

Microplate Devices, Uniplate 24 wells, 10 ml, Ref: 734-1217

Thermo Electron Corp. Heraeus Fresco 17, refrigerated centrifuge

Test Animals

All animal experiments were carried out according to the NationalInstitute of Health (NIH) guidelines for the care and use of laboratoryanimals, and approved by the National Animal Experiment Board, Finland.Male CD (Charles River Laboratories, Germany) at weight range of 200-250g (165-200 g upon arrival) were used for the experiments. Animals werehoused at a standard temperature (22±1° C.) and in a light-controlledenvironment (lights on from 7 am to 8 pm) with ad libitum access to foodand water.

Methods

Locomotor activity of the rats was tested in open field arena. The openfield test was performed during the rat light cycle and under a normallighting evenly distributed to the test chambers. The paths of the ratswere recorded by activity monitor (Med. Associates Inc.).

Dosing the vehicle, vehicle-amphetamine, (+)-α-DHTBZ or risperidone wasdone prior to LMA test. The rats were placed in the centre of the arena,and the path was recorded for 60 minutes.

Endpoint, Blood Samples and Tissue Processing

Within 10 minutes from the end of the test animals were euthanized by anoverdose of CO₂. The terminal blood sample was collected with cardiacpuncture from all compound treated rats from each group excludingvehicle rats. 0.5 ml of blood was collected with syringe attached to 18G needle and moved into precooled K2-EDTA microtubes. The EDTA microtubewas inverted several times to mix up the EDTA and blood. Tubes were thenimmediately put on wet ice and centrifuged (Heraeus Fresco 17) within10-15 minutes of collecting (9.6×1000 G/10×1000 RPM, +4° C. for 2 min),and 200 μl of plasma was collected in 96-tube plates (MatrixTechnologies ScreenMates 0.75 ml Alphanumeric Round-Bottom Storagetubes, PP) on dry ice according to sample map.

After collection of blood the neck was dislocated at the base of theskull. Brain was collected and weighed. Brain weights were recorded andthe brain was frozen on dry ice on the 24 well plate.

The plasma and brain samples were stored at −80° C. until sent foranalysis or destroyed.

Study 1

The effects on stereotypic behaviour and the distance travelled in ratsfollowing administration of (+)-α-dihydrotetrabenazine dosed at 0.5mg/kg to 2 mg/kg, as well as risperidone at 1 mg/kg, were studied.

Animals were grouped as follows:

-   -   Group 1: 10 rats treated with Vehicle (t=0 min) and Vehicle        (t=30 min)    -   Group 2: 10 rats treated with Vehicle (t=0 min) and Amphetamine        (t=30 min)    -   Group 3: 10 rats treated with (+)-α-DHTBZ 0.5 mg/kg (t=0 min)        and Amphetamine (t=30 min)    -   Group 4: 10 rats treated with (+)-α-DHTBZ 1 mg/kg (t=0 min) and        Amphetamine (t=30 min)    -   Group 5: 10 rats treated with (+)-α-DHTBZ 1.5 mg/kg (t=0 min)        and Amphetamine (t=30 min)    -   Group 6: 10 rats treated with (+)-α-DHTBZ 2 mg/kg (t=0 min) and        Amphetamine (t=30 min)    -   Group 7: 10 rats treated with risperidone 1 mg/kg (t=0 min) and        Amphetamine (t=30 min)

Results 1. Distance Travelled

Rats dosed with either vehicle, (+)-α-DHTBZ 0.5 mg/kg, (+)-α-DHTBZ 1mg/kg, (+)-α-DHTBZ 1.5 mg/kg, (+)-α-DHTBZ 2 mg/kg or Risperidone 1 mg/kgwere subjected to LMA testing first for 30 min and then for 60 minutesafter vehicle or amphetamine challenge. Resulting locomotor activity wasevaluated in 3 min bins and as a total over the testing period. Thenormalised total distance travelled over the testing time is presentedin FIG. 1.

When compared to the vehicle-vehicle group the vehicle-amphetamine wassignificantly different. When compared to vehicle-amphetamine group thevehicle-vehicle, (+)-α-DHTBZ 0.5 mg/kg, (+)-α-DHTBZ 1 mg/kg, (+)-α-DHTBZ1.5 mg/kg, (+)-α-DHTBZ 2 mg/kg and risperidone 1 mg/kg weresignificantly different.

2. Stereotypic Behaviour

Rats dosed with either vehicle, (+)-α-DHTBZ 0.5 mg/kg, (+)-α-DHTBZ 1mg/kg, (+)-α-DHTBZ 1.5 mg/kg, (+)-α-DHTBZ 2 mg/kg or Risperidone 1 mg/kgwere subjected to LMA testing first for 30 min and then for 60 minutesafter vehicle or amphetamine challenge. Resulting stereotypic activitywas evaluated in 3 min bins and as a total over the testing period. Thenormalised total stereotypic behaviour over the testing time ispresented in FIG. 2.

When compared to the vehicle-vehicle group the vehicle-amphetamine,(+)-α-DHTBZ 0.5 mg/kg and (+)-α-DHTBZ 1.5 mg/kg were significantlydifferent. When compared to vehicle-amphetamine group thevehicle-vehicle, (+)-α-DHTBZ 0.5 mg/kg, (+)-α-DHTBZ 1 mg/kg, (+)-α-DHTBZ1.5 mg/kg, (+)-α-DHTBZ 2 mg/kg and risperidone 1 mg/kg weresignificantly different.

Conclusions

This study evaluated the effect of (+)-α-DHTBZ at doses 0.5 mg/kg, 1mg/kg, 1.5 mg/kg and 2 mg/kg and risperidone at dose 1 mg/kg onamphetamine induced locomotor activity in male CD rats.

(+)-α-DHTBZ at all the tested doses and risperidone 1 mg/kg led to lowerlocomotor activity when compared to the vehicle-amphetamine group.(+)-α-DHTBZ at all the tested doses and risperidone 1 mg/kg led toreduced stereotypic behaviour when compared to the vehicle-amphetaminegroup. Both of the measured parameters suggest that (+)-α-DHTBZ has asedative effect similar to risperidone.

Study 2

The effects on stereotypic behaviour and the distance travelled in ratsfollowing administration of (+)-α-dihydrotetrabenazine dosed at 0.1mg/kg to 0.25 mg/kg, as well as risperidone at 1 mg/kg, were studied.

Animals were grouped as follows:

-   -   Group 1: 10 rats treated with Vehicle (t=0 min) and Vehicle        (t=30 min)    -   Group 2: 10 rats treated with Vehicle (t=0 min) and Amphetamine        (t=30 min)    -   Group 3: 10 rats treated with (+)-α-DHTBZ 0.1 mg/kg (t=0 min)        and Amphetamine (t=30 min)    -   Group 4: 10 rats treated with (+)-α-DHTBZ 0.25 mg/kg (t=0 min)        and Amphetamine (t=30 min)    -   Group 5: 10 rats treated with risperidone 1 mg/kg (t=0 min) and        Amphetamine (t=30 min)

Results 1 Distance Travelled

Rats dosed with either vehicle, (+)-α-DHTBZ 0.1 mg/kg, (+)-α-DHTBZ 0.25mg/kg, or Risperidone 1 mg/kg were subjected to LMA testing first for 30min and then for 60 minutes after vehicle or amphetamine challenge.Resulting locomotor activity was evaluated in 3 min bins and as a totalover the testing period. The normalised total distance travelled overthe testing time is presented in FIG. 3.

When compared to vehicle-amphetamine group the vehicle-vehicle,(+)-α-DHTBZ 0.25 mg/kg and risperidone 1 mg/kg were significantlydifferent.

2 Stereotypic Behaviour

Rats dosed with either vehicle, (+)-α-DHTBZ 0.1 mg/kg, (+)-α-DHTBZ 0.25mg/kg, or Risperidone 1 mg/kg were subjected to LMA testing first for 30min and then for 60 minutes after vehicle or amphetamine challenge.Resulting stereotypic activity was evaluated in 3 min bins and as atotal over the testing period. The normalised total stereotypicbehaviour over the testing time is presented in FIG. 4.

When compared to vehicle-amphetamine group the vehicle-vehicle,(+)-α-DHTBZ 0.1 mg/kg, (+)-α-DHTBZ 0.25 mg/kg and risperidone 1 mg/kgwere significantly different.

Conclusions

This study evaluated the effect of (+)-α-DHTBZ at doses of 0.1 mg/kg and0.25 mg/kg and risperidone at dose 1 mg/kg on amphetamine inducedlocomotor activity in male CD rats.

(+)-α-DHTBZ at 0.25 mg/kg and risperidone 1 mg/kg led to lower locomotoractivity when compared to the vehicle-amphetamine group. (+)-α-DHTBZ atboth the tested doses and risperidone 1 mg/kg led to reduced stereotypicbehaviour when compared to the vehicle-amphetamine group.

Study 3

The effects of (+)-α-dihydrotetrabenazine and risperidone on innon-amphetamine induced rats was studied. Animals were grouped asfollows:

-   -   Group 1: 10 rats treated with Vehicle    -   Group 2: 10 rats treated with (+)-α-DHTBZ 2.5 mg/kg    -   Group 3: 10 rats treated with (+)-α-DHTBZ 5 mg/kg    -   Group 4: 10 rats treated with risperidone 1 mg/kg

Results

In non-induced rats, the total movement and stereotypic behaviour inrats treated with the vehicle were comparable to(+)-α-dihydrotetrabenazine. However, rats treated with risperidone hadreduced total movement and reduced total stereotypic behaviour.

Comments

Studies 1 and 2 in Example 4 show the effectiveness of doses of(+)-α-dihydrotetrabenazine as low as 0.1 mg/kg in reducing movement inamphetamine-induced rats. It is therefore expected that such low doseregimes may also be useful in treating hyperkinetic movement disordersin humans.

Study 3 in Example 4 suggests that following administration of low dosesof (+)-α-dihydrotetrabenazine whereas abnormal movements of the typefound in movement disorders will be reduced or suppressed by the drug,normal movements will not be. This is in contrast to risperidone, awell-used treatment for movement disorders, where the levels of bothnormal and abnormal movements can be reduced by administration of thedrug.

Example 5

The objectives of this study were to provide plasma samples in order todetermine the pharmacokinetic parameters of (+)-α-dihydrotetrabenazinefollowing oral administration of (+)-α-dihydrotetrabenazine and itssuccinate salt to 3 male non-naive Beagle dogs (strain HsdRcc:DOBE), ata dose level of 1.50 mg/kg.

Each dog weighed approximately 9.0 to 12.0 kg and was approximately 16to 18 months of age on the first day of dosing. Each dog was uniquelyidentified by indelible tattoo number.

The dogs were last used approximately 1 to 6 months prior to dosing thisstudy. Dogs were purpose-bred, socialised and vaccinated forconventional multidisciplinary biomedical research at Envigo UK Limited,Hillcrest Research Station, Belton, Loughborough.

Prior to commencement of each dosing session, each dog was examined by aqualified Veterinary Surgeon for suitability for the study. Copies ofthe health and weight records of each animal were retained in the studyfile. Dogs were allocated to the study 5 days prior to dosing and wereacclimatised in the study unit.

During the acclimatisation and study periods, the dogs were housed inpairs in purpose designed pens constructed of galvanised steel withsmooth concrete floors lined with wood shavings (certificates ofanalysis retained in study file). The pen area was maintained at atarget temperature range of 14-26° C. and was exposed to 12 hoursfluorescent lighting (08:00-20:00) followed by 12 hours dark per day.

Environmental readings (temperature and humidity) were recorded dailythroughout the acclimatisation and experimental period.

Administration of (+)-α-Dihydrotetrabenazine Succinate Salt

The day prior to dosing, 93.7 mg of (+)-α-dihydrotetrabenazine succinatesalt (68.9 mg (+)-α-dihydrotetrabenazine freebase equivalent) wasaccurately weighed and then placed into a suitably sized container. Onthe morning of dosing, 91.87 mL of methyl cellulose solution (0.5% aq.w/v) was added to the (+)-α-dihydrotetrabenazine succinate salt and thensonicated for ca. 5 minutes at ambient temperature, prior to beingstirred at room temperature for ca. 15 minutes. The final dose yielded aclear solution containing (+)-α-dihydrotetrabenazine succinate salt attarget concentration of 0.75 mg/mL dihydrotetrabenazine freebaseequivalent.

Doses were administered orally, via gavage, at a dose volume of 2.00mL/kg yielding the target dose level of 1.50 mg/kg. Following dosing, 10mL of tap water was flushed down the gavage to ensure the entire dosewas dispensed.

Following dosing over four sessions each with one of the test materials,serial whole blood samples (circa. 1.3 mL) were collected from a jugularvein then placed into K₂ EDTA treated tubes pre-dose and then 0.25,0.50, 1, 2, 3, 4, 6, 12 and 24 hours post dose.

Blood samples were placed immediately on a cool-block before beingcentrifuged within 15 minutes at 3,000×g, 10 minutes, 4° C. andresultant plasma drawn off.

Administration of (+)-α-Dihydrotetrabenazine

The day prior to dosing, 72.9 mg of (+)-α-dihydrotetrabenazine wasaccurately weighed then placed into a suitably sized container. On themorning of dosing, 97.23 mL of methyl cellulose solution (0.5% aq. w/v)was added to the test material then sonicated for ca. 5 minutes atambient temperature, prior to being stirred at room temperature for ca.10 minutes. The final dose yielded a very fine homogenous suspensioncontaining (+)-α-dihydrotetrabenazine at target concentration of 0.75mg/mL which was constantly stirred throughout the dosing period.

Doses were administered orally, via gavage, at a dose volume of 2.00mL/kg yielding the target dose level of 1.50 mg/kg. Following dosing, 10mL of tap water was flushed down the gavage to ensure the entire dosewas dispensed.

Following dosing over four sessions each with one of the test materials,serial whole blood samples (circa. 1.3 mL) were collected from a jugularvein then placed into K₂ EDTA treated tubes pre-dose and then 0.25,0.50, 1, 2, 3, 4, 6, 12 and 24 hours post dose.

Blood samples were placed immediately on a cool-block before beingcentrifuged within 15 minutes at 3,000×g, 10 minutes, 4° C. andresultant plasma drawn off.

Results

The (+)-α-dihydrotetrabenazine plasma concentrations are shown in Tables3 and 4 below.

Table 3 shows the plasma concentrations of (+)-α-dihydrotetrabenazine inthe male Beagle dogs following oral administration of(+)α-dihydrotetrabenazine succinate salt at a dose level of 1.50 mg/kg(dihydro tetrabenazine freebase equivalent).

TABLE 3 Time Point Plasma concentration (ng/mL) (Hrs.) Male 1 Male 2Male 3 Mean SD 0 BLQ BLQ BLQ 0.00 0.00 0.25 66.7 43.2 28.0 45.97 19.500.5 47.6 32.4 83.1 54.37 26.02 1 23.4 14.8 49.2 29.13 17.90 2 7.04 3.6521.7 10.80 9.59 3 2.48 1.23 10.6 4.77 5.09 4 1.03 0.531 6.21 2.59 3.14 60.304 BLQ 1.68 0.66 0.90 12 BLQ BLQ 0.212 0.07 0.12 24 BLQ BLQ BLQ 0.000.00 BLQ—Below the limit of quantitation (<0.10 ng/mL) BLQ values aretreated as zero for the purposes of calculating the mean and SD values

Table 4 shows the plasma concentrations of (+)-α-dihydrotetrabenazine inthe male Beagle dog following oral administration of(+)-α-dihydrotetrabenazine at a dose level of 1.50 mg/kg

TABLE 4 Time Point Plasma concentration (ng/mL) (Hrs.) Male 1 Male 2Male 3 Mean SD 0 BLQ BLQ BLQ 0.00 0.00 0.25 48.9 20.2 107 58.70 44.220.5 39.2 18.3 65.0 40.83 23.39 1 24.2 9.63 40.5 24.78 15.44 2 7.21 2.7217.2 9.04 7.41 3 2.51 0.798 9.72 4.34 4.73 4 1.04 0.359 4.73 2.04 2.35 60.367 0.113 1.42 0.63 0.69 12 BLQ BLQ 0.168 0.06 0.10 24 BLQ BLQ BLQ0.00 0.00 BLQ—Below the limit of quantitation (<0.10 ng/mL) BLQ valuesare treated as zero for the purposes of calculating the mean and SDvalues

Following administration of (+)-α-dihydrotetrabenazine succinate salt, amean C_(max) blood plasma concentration of (+)-α-dihydrotetrabenazine of64.33 ng/mL was observed on average 0.33 hours post dose with thecorresponding exposure being 71.8782 ng·h·mL.

(+)-α-dihydrotetrabenazine resulted in similar results to(+)-α-dihydrotetrabenazine succinate salt with a(+)-α-dihydrotetrabenazine C_(max) of 58.7 ng/mL, observed at 0.25 hourpost dose, with a mean exposure being 64.26 ng·h·mL.

Comments

These studies show that (+)-α-dihydrotetrabenazine succinate salt can beconverted in vivo to (+)-α-dihydrotetrabenazine and provides(+)-α-dihydrotetrabenazine blood plasma levels comparable to thoseobtained when (+)-α-dihydrotetrabenazine free base is administered.

EQUIVALENTS

It will readily be apparent that numerous modifications and alterationsmay be made to the specific embodiments of the invention described abovewithout departing from the principles underlying the invention. All suchmodifications and alterations are intended to be embraced by thisapplication.

1. A method of treatment of a movement disorder in a subject in needthereof, which method comprises administering to the subject atherapeutically effective amount of (+)-α-dihydrotetrabenazinesuccinate.
 2. A method according to claim 1 wherein the movementdisorder is a hyperkinetic movement disorder.
 3. A method according toclaim 2 wherein the hyperkinetic movement disorder is selected fromHuntington's disease, hemiballismus, senile chorea, tic disorders,tardive dyskinesia, dystonia and Tourette's syndrome.
 4. A methodaccording to claim 3 wherein the hyperkinetic movement disorder isTourette's syndrome.
 5. A method according to claim 1 wherein thesubject is a mammalian subject.
 6. A method according to claim 5 whereinthe subject is a human.
 7. A method according to claim 1 wherein thetreatment comprises administering to the subject an amount of(+)-α-dihydrotetrabenazine succinate between 1 mg and 30 mg per day. 8.A method according to claim 7 wherein the treatment comprisesadministering to the subject an amount of (+)-α-dihydrotetrabenazinesuccinate between 2 mg and 20 mg per day.
 9. A method according to claim1 wherein the (+)-α-dihydrotetrabenazine succinate salt is in acrystalline form.
 10. A method according to claim 1 wherein the(+)-α-dihydrotetrabenazine succinate salt has a salt ratio ofapproximately 1:1.
 11. A method according to claim 1 wherein the(+)-α-dihydrotetrabenazine succinate salt is in a substantiallycrystalline form having an X-ray powder diffraction patterncharacterized by the presence of major peaks at the diffraction anglesof approximately 9.2° and/or 10.0° and/or 18.5° and/or 22.4°.
 12. Amethod according to claim 1 wherein the (+)-α-dihydrotetrabenazinesuccinate salt is in a substantially crystalline form having an X-raypowder diffraction pattern substantially as shown in any of plotsZEN-E-6-7b, LYO-F-4(3), SUN-AJ-163(2) or SUN-AJ-163(2) AD in FIG.
 1. 13.A method according to claim 1 wherein the (+)-α-dihydrotetrabenazinesuccinate salt is in a substantially crystalline form having an X-raypowder diffraction pattern substantially as shown in plot SUN-AJ-163(2)in FIG.
 1. 14. A method according to claim 10 wherein the movementdisorder is a hyperkinetic movement disorder.
 15. A method according toclaim 14 wherein the hyperkinetic movement disorder is selected fromHuntington's disease, hemiballismus, senile chorea, tic disorders,tardive dyskinesia, dystonia and Tourette's syndrome.
 16. A methodaccording to claim 15 wherein the hyperkinetic movement disorder isTourette's syndrome.